- Any case where the victim was engaged/married and it turns out their killer was their in-laws and the widow had no idea. How must it feel to find out that your family killed the person you loved?
- "Friends & Lovers" details the mystery of a young man by the name of Eric found naked and smothered to death in the middle of the desert. As it turns out, he and his best friend Bobby Taylor attended a concert, where they ingested hallucinogens and experienced a very bad trip. Bobby, suffering from auditory hallucinations caused by the music and Eric's screaming, accidentally smothered Eric to death trying to make it stop. Upon revealing this to Bobby, the poor man is devastated, and, when his lawyer tries to convince him to plead on diminished capacity, he has but this to say:Bobby Taylor: You don't understand...I don't care what happens to me. I killed my best friend.
- This case hits Grissom hard, and after Bobby is booked, he goes to an amusement park and boards the roller coaster, not to enjoy himself, but to clear his head. His stony, intense expression as the roller coaster rockets through the course makes it clear how deeply cases like this affect him, how much he wishes he could just forget it and leave it all behind, but he can't. He won't.
- Sara crying in "Too Tough to Die" as she tells Grissom that the victim's husband doesn't seem to realise that his wife will be in a vegetative state for the rest of her life and wonders what kind of system punishes the victim for not dying.
- The team has to look into the death of a baby that had been left inside of a car during a heatwave. During the investigation, they discover that the parents had already lost a child to a genetic disease/disorder that he had inherited from them and that their current child was starting to display the same symptoms. Unwilling to go through the pain of watching another child suffer and die, the parents came up with the plan to put their baby to sleep and leave him in the car. The worse part of all this? The baby was actually having a bad reaction to the fertilizer the wife was using in her gardening business and coming home with traces of it on her. If they had just waited a few days for the test results to come back, they would've known this. As Catherine put it: "[They] killed a perfectly healthy baby." Their reaction to this revelation is absolutely heartrending.
- Grissom's speech to the killer in Butterflied. After four seasons, it was finally confirmed that he was romantically interested in Sara, he was just too afraid to do anything about it. Worse, Sara is revealed to have heard the whole thing behind the interrogation room glass.Grissom: It's sad, isn't it, doc? Guys like us. Couple of middle-aged men who've allowed their work to consume their lives. The only time we ever touch other people is when we're wearing our latex gloves. We wake up one day and realize that for fifty years we haven't really lived at all. But then, all of a sudden we get a second chance. Somebody young and beautiful shows up. Somebody...we could care about. She offers us a new life with her. But we have a big decision to make, right? Because we have to risk everything we've worked for in order to have her. I couldn't do it. But you did. You risked it all. And she showed you a wonderful life, didn't she? But then she took it away and gave it to somebody else...and you were lost.
- In the episode "Harvest", a young man, Daniel, is dying of leukemia, but surviving thanks to bone marrow transplants and blood transfusions from his younger sister, Alicia. He can't stand seeing her suffer for his sake, so he asks his parents to stop, but they refuse after his kidneys start to fail. Daniel ends up poisoning Alicia so she wouldn't suffer any more. Grissom points out he'll be arrested for murder, but Daniel only has six months to live, so he won't even survive to see the trial.Grissom: This wasn't a mercy killing, Daniel. This was an execution. Bone marrow, transfusions... that's her blood in your veins. It dripped out of your nose onto the blanket while you were killing her. If you cared so much for Alicia, why didn't you take your own life instead of hers?Daniel: Suicide isn't an option. It's an unforgivable sin in the eyes of God.Grissom: But you believe that your God forgives murder? If that's your defense, it won't keep you out of jail.Daniel: But my death will. See, I've got about six more months. I'll be dead before there's even a trial. I... I do want to thank you, though.Grissom: For what?Daniel: For speaking for Alicia. You're probably the first person in her life to think only of her. You know, you may not believe in God, sir, but you do his work.
- The situation that lead to the death of Jerry Gable, the victim in Dog Eat Dog. Jerry suffered from Prader Willi Syndrome, which prevents the stomach from signaling the brain that it's full, so Jerry felt like he was hungry all the time. This caused Jerry to die from overeating. Even viewers who don't have eating disorders can't help but pity Jerry in the end.
- Grissom's horrified realisation of why Sara has been abducted by the Miniature Killer.Grissom: This girl holds me responsible for the death of Ernie Dell. I took away the only person she ever loved, so she's gonna do the same thing to me.
- Grissom interrogating the Miniature Killer, ending with him outright begging her to tell him where Sara is.
- The Death of Warrick Brown in the first episode of Season 9. Everyone is falling apart and saddened by the loss of their comrade, and Grissom wanted to hold him tight enough to keep him alive. It was a tragic loss with how everyone was dealing with it.
- The video game Deadly Intent references this with the player character being compared positively to Warrick; most fans would find themselves stabbed in the feels when the comparison is made.
- In "Say Uncle", Grissom investigates a double homicide where a Korean man and woman apparently killed each other. It's revealed the woman has an eight-year-old son, Park, who watched her shoot the man, who turns out to be Park's uncle who was recently released from prison. He and Park's deceased father were gangsters, and it also comes to light that both Park and his mother, who was a junkie, are HIV positive. Park's mother put him in a medically unsound (and painful) clinical trial, with his doctor giving him a gastric bypass tube. When Park's uncle found out about this, he tried to take Park away from his mother, who hunted them down and shot the uncle... Then Park, driven over the Despair Event Horizon, took his uncle's gun and shot his own mother to death. As Brass puts it, Park didn't have any control over his own life until he picked up that gun, and the episode closes with an eight-year-old boy going off to juvenile detention. It's not often a CSI regrets solving a case, but in this episode, it's easy to see why Grissom is so deeply affected.
- Nick breaking down at the end of "Turn Turn Turn" as he tells Langston that he can hear Haley asking what happened. Langston can only console him by saying that Haley died due to events that were set in motion before she was ever born.
- In "Mascara", Langston finding his book that he autographed for his star student, now dead. It read:Langston: To Silvia, when you get published... I will expect your autograph. Your fan, Raymond Langston.
- What's sadder is that the student could have easily been saved. Earlier, she was drugged while trying to investigate a series of serial killings. She stumbled across a busy street trying to flag a car to help her, but they all turned her away, and in the end, the serial killer caught up and strangled her.
- In "Death and the Maiden, a young man is sodomized by his girlfriend's abusive and controlling brother for having sex with her, as he wanted her to remain a virgin forever. It emotionally destroyed him, to the degree that he sees his rapist's face whenever he looks at his girlfriend. There is a Hope Spot as Nick tries to convince him that it wasn't his fault and none of it would matter if he loves her. He sees his girlfriend trying to hug him, before pushing her aside and walking away, as Nick shakes his head.
- In "The Lost Girls", a weather girl alone in Vega is lured away by a pimp, raped, and forced into prostitution, before her dead body was found at her first night at "work". Her killer? A top "wifey" of the pimp who herself was abused by several previous pimps and trafficked around, becoming so traumatized that she actually believed her latest pimp's lies about genuinely loving her, which he tells to all his new victims. When the wifey was beaten with a baseball bat by the pimp for calling her from the police station, she blamed herself. And when the weather girl tried to escape and convince the her to come with, the wifey is so caught up by the trauma and lies that she killed her in rage.
- The episode's other plot is the last of a Crossover between the three CSI series, involving the search for a girl named Madeline Briggs who was trafficked across the three cities. She was last sold to the same pimp, and when he discovered that she was pregnant he severely beat her to induce Forced Miscarriage. Langston tracked down Madeline by texting all of the pimp's girls, asking her to come home, and all the other girls simply close their phones and return to their tricks, but at least Madeline is found safe.
- In "Lost & Found", a father, daughter, and son went missing, and the mother spent the last three years looking for them. Eventually, the team found the son's corpse hidden inside the house, and the father and daughter living as a couple under a false identity, together with the daughter's own son. The father confessed that he killed his son and impregnated his daughter. In grief, the mother takes a cop's gun and shoots the father dead, only for the team to find out later that it was the uncle that molested the daughter, who then accidentally killed her brother when he threatened to tell the mother. The father actually took her into hiding to protect her. All in all, the poor girl ends with two relatives dead, and another two facing jail.
- In "Pool Shark", the episode where Wendy Simms is Put on a Bus, Simms reveals to her crush David Hodges that she is leaving the lab for good and moving to Oregon, and deliberately tells him last, knowing full well that he would try to convince her to stay. Simms gives Hodges a tearful hug, and he is visibly devastated.
- "Sqweegel" has the titled killer threatening people with dark secrets, warning that if they don't confess, his next visit would result in their deaths. Two of his victims include a paramedic who deliberately started fires, and a moral crusader who cheats on her husband behind his back. The third victim is a wealthy philanthropist (played by Ann-Margret) who tearfully confessed her dark secret - that she mercy killed her disabled son upon his request, so he doesn't have to live in pain anymore.
- The very end of "Cold Blooded", where Carly Beck finally gets closure over her missing daughter.
- "Unleashed" has a women's shelter worker disappearing and turning up as a Human Pet for a rich dentist, pretending to be a cat. Her colleague, who she once rescued from domestic abuse, tried to "rescue" her from what she thought was an abusive situation, not realizing that all of it was consensual. As a result, her friend died from struggling during the Unwanted Rescue operation.
- The B-plot of the episode involves a pregnant student hanging herself as a result of trauma from breaking up with her boyfriend, her father's death, and the bullying she endured from his ex-girlfriend and her fellow cheerleaders, who leaked her cheerleading tryout video which went viral. Doc and Nick were too late to save her, but at least managed to save her baby and get the poor girl's bullies arrested.
- "Dead of the Class" has a once bullied student turned teacher for troubled students trying to use a school reunion to correct a mistake he made years ago - defusing a bomb he planted as a student with liquid nitrogen, so that it won't accidentally go off. Unfortunately, the former prom queen walked by and he accidentally spilled liquid nitrogen down her throat, so he tried to save her with an emergency tracheotomy but was too late. His friend was the former valedictorian who broke down after experiencing the cutthroat nature of law firms, where looks advanced careers more than talent, and quit to become the school lunch lady. She convinced the teacher to not report to the police but instead frame the former school jock for the death, and as a result both of them are looking at manslaughter and obstruction of justice charges over a tragic accident.
- Jim learning his daughter was a murderer in "The Devil and D.B. Russell". When she confronts him, he says she can shoot him. He's already dead inside.
- "The Fallen" has DB trying in vain to stop a SWAT team from killing a troubled teen who held up a police station, who he just convinced to surrender. The cops thought he was reaching for his gun, but in fact he was reaching for his St. Christopher medal. Turns out he was manipulated by a Dirty Cop who used him to kill her husband, who is also a cop, and injuring many others.
- "Let's Make A Deal" has Nick sombrely arresting an inmate who strangled another inmate to death, not because he was an informant, but because he molested him years ago while serving as a school janitor. Nick reflects to his own sexual assault at the hands of a replacement babysitter, and said he would have done the same thing if he ran into his molester. Considering the inmate only ended up in the same room as the molester by accident and didn't plan the murder, one can only hope the courts went easy on him.
- In "Immortality", Grissom tells the bomber about a whale that sings at a frequency that none of the other members of his species can hear. The story of the whale is sad enough, but by the end of the sequence of scenes, it's obvious that he's talking about himself and Sara.
- Morgan sobbing hysterically as she, Greg and Catherine are about to try to disarm the bombs. And Catherine shouting that she loves them right before they make their attempt at disarming the bombs, knowing that if they fail, this will be the last thing she ever says to them.
- Due to the cancellation of the series, it is revealed that Julie Finlay died from her wounds at the hands of the Gig Harbor Killer at the end of season 15, with D.B. having a plaque of her in his procession.
2021 Revival
- Catching up with some of the old crew and seeing how time has treated them: Jim Brass is almost completely blind and only has his pet parrot to keep him company.
- At the end of the first episode of the revival, David Hodges is implicated with charges of corruption and falsifying evidence. Whether or not he actually did it or he's being framed, hundreds of convictions are in danger of being overturned and so many criminals might be released, while everyone he ever worked with will face the consequences in one way or another.
- Episode 2 "Honeymoon in Vegas": Hodges turns himself in to the police after the charges are filed, and he has a quietly devastated face visible the entire time. His life is crashing down around him, and later Jim and Grissom openly tell him that they don't disbelieve he could actually have done what he's accused of. It's clear he's very hurt that they doubt his word about being framed, and he feels abandoned by people he's known for years.
- Grissom, who lives his entire life by the mantra "the evidence never lies" is clearly affected now being in a world where people dismiss "empirical science as just someone's opinion."
