Major plot points and spoilers are to be marked.
- The blood-curdling shooting of Kima Greggs. She's undercover and lost at night on the back of Orlando's car when they are battered with gunfire. Everything is caught on tape and replayed on the next episode.
- Made even worse by McNulty being covered in her blood. This belligerent wise ass breaks down blaming himself for what happened to Kima. Maj. Rawls calls him on this, saying that if he were actually the one to blame, Rawls himself would be the first to tell him.
- Freamon shows up at the crime scene to prompt the Major Crimes detectives into running the wiretap. Every detective tells him to go fuck himself until he makes them realize that the shooters are the guys that they have under surveillance, to which everyone rises up enthusiastically.
- Wee-Bey's reaction to being informed that one of the victims of the shooting is a cop is one of the biggest reaction faces of all time. 
- The brutal murder of Brandon. Considering that his maimed corpse is left at the front of Wallace's house (Wallace being the one that ratted Brandon out to Stringer Bell), he is left broken and traumatized, and he begins a spiraling descent into drug abuse.
- Omar's reaction upon seeing the damage done to Brandon is a painful and shattered wail from seeing a loved one completely destroyed.
- Shardenne finding out that her friend and fellow stripper Keesha had been discarded like trash when she overdosed at a party that Avon's lieutenants threw for D'Angelo. This finally makes her break down, cut off all relationship with D'Angelo, who told her that they had taken her to the hospital where she died, and finally collaborate with the police. She becomes a reliable source for information on various investigations involving women trafficking.
- Stringer talking Bodie into killing Wallace. Bodie almost didn't pull the trigger after hearing Wallace's pleas.
- D'Angelo's reaction to this with Stringer and Levy:
WHERE THE FUCK IS WALLACE!
- This whole conversation is heartbreaking. We've seen the cracks forming in D'Angelo's trust in the Barksdale Organization. He agreed to take the 20 years rap for the murder, but it took an awful lot of convincing. And now, here in prison meeting with Stringer and Levy, the dawning realization that they just consider D'Angelo a pawn in their game is pretty heartbreaking. He goes from softly asking "Where's the boy, String?" to flat-out screaming in the end.
- The weaning quality of the Barksdale product plus the apparent loss of street power since Avon's arrest, leads to a shootout between a Barksdale crew and an invading independent crew leads to the death of a schoolboy who was just getting ready to go to class.
- Ziggy shooting down Glekas in cold blood. Ziggy spends the majority of the season trying to prove himself a badass. When he realizes what he has done, he cannot contain his own tears and breaks down; he immediately turns himself in and signs a confession, guaranteeing that he would spend his life in jail.
- The murder of D'Angelo at jail.
- Beadie pleading with Frank to turn himself in. All his work has been turned upside down, his reputation shattered and his beloved docks are on the road to become high-end condominiums. In tears, Beadie makes him realize just how low he has fallen and he makes an effort for her not to see him crying.
- Frank Sobotka's death. The Greek is informed that Frank turned snitch. Frank thinks that he is about to break a deal with The Greek and then, the screen fades to black. He washes up at the docks, throat slit and covered in stab wounds. Just seeing Nick and Beadie react to that sight is... damn.
- Made worse by the fact that Ziggy signed a confession for the murder of Glekas; by doing this, not even The Greek or Spiros Vondas would have been able to do anything to take him out of jail, making Frank's death a specially unnecessary tragedy.
- Made even worse with Frank not actually telling anything to the police prior to the meeting under the bridge by a mere technicality, since he turned himself in without legal representation to legitimize his collaboration with the authorities. Oops!
- The way the entire group of stevedores stands around as Frank's body is brought out of the water, just standing there in stunned silence like a gigantic family that suddenly just their father. And the audience doing a rewatch knows that this particular moment would more or less be the last moment all those stevedores were together, and that many of their lives would be wrecked because of Sobotka's death... it's just tragic all around.
- "Your way, it won't work."
- The hit on Omar and his grandmother on a church day under orders by Stringer Bell, which is decried by everyone who finds out (even Stringer). This finally provides Omar an excuse to finally kill him.
- The death of Stringer Bell. Damn if he asked for it, but he was one of the best characters in the whole show!
- Even Evil Has Loved Ones Donnette is seen crying over a picture of him in the end montage
- His confession of the murder of D'Angelo to Avon is no less a shock.
- McNulty shaming Briana Barksdale for the murder of D'Angelo. Briana asks him why didn't he inform her before going to Donette, considering that Briana is D'Angelo's mother; in simple words, McNulty tells her that he informed Donette because he was hoping that she actually cared for D'Angelo, concluding that Briana didn't care as she was the one that convinced D'Angelo not to testify and to take the 20 year sentence for the sake of Avon. Briana breaks all relations with Avon and Stringer because of this, though she is left in charge of the remnants of the organization after the latter two are taken out of the picture.
- Prez's shooting of a fellow officer. He's finally managed to acquire some respect as an investigator, but the minute he steps into the street he effectively ends his own career as a policeman. It's so surprising and sad that basically everyone in Homicide is completely aghast to what they're supposed to do until Daniels shows up and tries to talk to Prez. The episode ends with Prez sitting alone in the dark by the computers of the MCU and hearing the wiretap noises by the last time, knowing he's never going to do that kind of work anymore.
- Cutty reminiscing about Bodie being in diapers and the times he sparred with Bodie's older brother James back in the day, only to learn that "James been dead"
- A distraught Avon realizing too late that Stringer meant much more to him than having more or fewer corners.
- The end of Hamsterdam and Colvin being thrown under the bus for an iniciative that greatly improved the lives of the people. Made more sad by the final scene; an afflicted Colvin stands in front of the ruins of his utopia, while Bubbles recalls the good old days in the free zones.
- The story of Old Face Andre, a minor player and store owner who guards a stash and is pinballed between Omar, Marlo, and Proposition Joe in a tragic game. His anguised voice and denied plea not to be killed where his people won't find him makes his demise rather poignant.
- Prez listening to Johnny Cash while cleaning bubble gum from below school chairs, a sad Call Back to his glory days as analyst in the Sobotka case.
- The entirety of the kids' plot on Season 4 is a giant tear jerker on its own.
- The high-pressure kettle that Little Kevin exploded for everyone involved. Tasked to send Lex to his death under the pretext of meeting a girl, Little Kevin sends Randy in his stead. When Randy gets in trouble at school, he pleads for leniency on the fact that he knows about Lex' murder. In a mistake at the police, Detective Herc Hauk reveals to Little Kevin that Randy has been in contact with the police; at first, Kevin does not intend to do anything regarding the incident, but he is warned by his crew fellows that he should talk with Marlo on why he himself was talking to the police. Kevin drops Randy's name as the probable loose cannon, but Kevin is still killed for creating it by being lazy. The whole thing sparks the investigation of the vacant house murders; in disgust for Kevin's murder, Bodie begins talking with the police himself, which in turn gets him killed.
- Colvin's plea to Wee-Bey to let go of Namond so he can provide him with the bright future he deserves. The great thing comes from the fact that Namond can finally be rid of the bitch of a mother he has. It's tremendously satisfying that a murderous psychopath like Wee-Bey at least is made to realize that he doesn't want his life imposed on his own son.
- Randy chastising Carver for unwittingly allowing Marlo's crew burn down his house and nearly killing his step-mother is one of the most memorable scenes of the series.
- "You're gonna help, huh? You're gonna look out for me? You're gonna look out for me, sergeant Carver? You mean it? You're gonna look out for ME? You promise? You got my back, huh?"
- At the next episode, Randy finally understands that there is a reason why Carver failed him in how the system caved in on both of them in spite of Carver's best efforts. Though he stops holding Carver as personally responsible, Randy still has his life destroyed by the stupidity of the police system.
- Carver's fight to help Randy is tear jerky enough. Carver finally realizes that his hands-off approach to policing would end up paying a terrible price by unwittingly destroying Randy's life. To a lesser degree, Herc is also responsible for Randy's downfall in a series of mistakes that end up costing him his job as a detective and he is eventually kicked off the force.
- "It's ok, you don't need to feel bad. You tried. Thanks." -pats him on the arm-
- Michael's inability to trust or even share a quiet moment with a caring adult figure like Dennis is pretty sad on its own, but it's made worse when this pushes him into becoming another murderer of the Stanfield gang. It's really heartbreaking to realize that he feels they are the only people he can relate to.
- Chris Partlow's reaction when Michael told him that his stepfather molested him when he was little and that his little brother would be in the same danger is brutal. The retribution that the guy received from Partlow is bloody and painful to say the least, implying that Partlow was molested too when he himself was little.
- Bodie realizing that Little Kevin is gone because he told the guy to come clean to Marlo in the first place
- The death of Bodie. He went out like a soldier.
- McNulty learning that Bodie died because Jimmy reached out to him.
- Bubbles' multiple instances of being a victim of bullying from a dope fiend make him realize just how unreliable Herc wound up being. Once he rids himself from his reliance on the police, Bubbles takes it a step too far, causing accidental manslaughter of Sherrod with a poisoned vial intended for his bully. Landsman takes pity to Bubbles and sends him to suicide watch into a psych ward. When Waylon visits Bubbles, now detoxed and clean, the latter breaks down at his sight out of shame.
- The torture and murder of Butchie. Realizing that he's Omar's bank, Marlo orders his murder to fish out Omar out of hiding.
- The betrayal and assassination of Proposition Joe by his nephew and lieutenant Cheese Wagstaff. Cheese sets up the meeting between Marlo and the Greek so that Joe is left out, since he's grown tired of his preachy platitudes and passiveness; when Joe is trying to flee Omar's retribution for the death of Butchie, Cheese abandons the room on a paltry excuse and Prop Joe is ambushed and killed by Marlo. Cheese eventually faces retribution from Slim Charles, a former lieutenant of Prop Joe, who kills Cheese due to his disloyalty and flaunting. Eventually, Charles takes over the contact with the Greek when Marlo is taken out of the game.
- The death of Omar himself. He's been terrorizing drug dealers for years and is regarded as a living legend worthy of fear and awe. It's bad enough that he's killed by a kid that used to idolize him, but in a matter of hours after his death, he becomes just another statistic.
- This turnout also puts the entire idea of "street cred" or a reputation in context: his death is deemed not even newsworthy, and the coroner nearly mixes up his information with another body's. To the rabble he is a legend, but almost nobody above the street has any idea who this otherwise feared, respected man is.
- The transformation of Randy Wagstaff by the time Bunk visits him again. This was a wide-eyed boy who found himself as the sole witness of a murder investigation and to whom the police catastrophically failed to protect. When Bunk visits him, he is a teenager that is so chewed up by the foster home system that he shows nothing but calm rage at Bunk, reminding him of the empty promises made by the police and is even offended at the mere suggestion that they would ask for help yet again with nothing to bargain in return. With no reason whatsoever to trust the police, Randy scoffs at Bunk and leaves him empty-handed.
- Randy even scoffs at Bunk for not even offering to get him out of the foster system; though he knows that he's holding vital information, Randy has no reason to disclose it, especially after the police had the nerve of showing up one year later.
- The death of Snoop. She's a murderous little shit, but damn if she isn't one of the best characters in the whole series! Michael proves himself wise enough not to go unarmed to wherever she's taking him. She even asks Michael if she looks pretty before he shoots her.
- Dukie's downfall into drug addiction. After realizing he's pretty much useless in everything he attempts to do, he decides to basically destroy every relationship that he used to have; he even betrays Prez's confidence by tricking him out of money to buy drugs. He basically becomes the next Bubbles.
Dukie: You remember that one day, summer past
? When we threw them piss balloons at them terrace boys. You remember? Just before school started up again... Y'know, I took a beatdown from them boys, I don't even throw a shadow on it. That was a day... Y'all bought me ice cream off the truck. You remember, Mike? Mike: I don't
- Bubbles' clean-up act has almost come full circle except his coming to terms with his causing Sherrod's death. At the support meeting, Bubbles finally admits that he was fortunate to have been given a second opportunity and that he will have to live his life in a better fashion, culminating with his sister regaining her trust for him by letting him dine with her upstairs as a proper family circle.
- Michael's farewell to his little brother Bug is a huge tear jerker on its own. He has become a target by betraying Marlo's organization, so he sends Bug to live with his aunt. Bug can hardly hold the tears, while Michael struggles with the waterworks himself. After this, Michael becomes the next Omar.