Murphy‘s partner and best friend is unceremoniously gunned down by La Quica in the pilot.
Murphy testifies against him in court, believing his friend will get justice but Quica is immediately bailed out by Pablo.
Pablo's humiliation during his first day at the Senate, which immediately causes the series of Disaster Dominoes that ultimately costs the lives of tens of thousands of people.
The assasination of Rodrigo Lara who was shown to be one of the most honest and well-intentioned politicians in the whole series.
Made even more poignant by how he didn’t wear the bulletproof vest Murphy gave him. While it’s likely that it wouldn’t have helped, Murphy still blames himself.
Diana Turbay's death by Friendly Fire in a botched rescue attempt, along with the surprisingly friendly guard who kept her company and went down fighting. Her death proves to be the last straw that forces President Gaviria to agree to Pablo's surrender terms to stop further bloodshed.
Gustavo's death. He may be a crook like Pablo, but he has always been the more reasonable and merciful one of the two. His death is depicted rather sympathetically with him choosing death over betraying his cousin. It's telling that even though Steve's narration says there is no honor among thieves, Gustavo is definitely one of the few who do have some.
Gustavo: We are bandits... not snitches.
There is also the fact that Gustavo's death marks the beginning of Pablo's Sanity Slippage. Without his cousin's reasonable counsel, Pablo goes down a much darker path that none of them could have ever imagined.
The family's reaction to Gustavo's death is... somber to say the least. For the first time ever, we see Hermandila breaks down and gets angry at someone out of grief. Pablo spends some time just aimlessly staring at the mountain when the two of them used to go biking as children.
The escape of Pablo Escobar after the nightmare which he put the country through.
Season 2
Colonel Carrillo is ambushed and killed by Escobar.
Vice-minister Sandoval falls on his sword to protect Gaviria.
When Manuella asks her father how Santa will find them, having moved to another safehouse after the Los Pepes attack resulting in the death of Carlos. Escobar, his face trembling, barely holds back the tears.
Fernando Duque’s death. Duque was an Amoral Attorney but it had been made pretty clear that he wanted to leave Pablo a long time ago but was forced to continue. Just as it seemed like he would finally be able to escape this nightmare through his deal with Pena he was brutally murdered by Los Pepes. Made even worse by the fact that his son, who he took with him in an attempt to protect him, was murdered alongside him.
Maritza's death at the hands of her childhood friend Limon, who at this point has completely submitted himself to Pablo's cause and shoots her in cold blood and takes her last stack of money, abandoning her now orphaned baby behind.
Pablo's conversation with Gustavo's ghost is incredibly poignant, especially the conclusion.
Pablo: Everything went to shit the day you went away. Gustavo: So, do you miss me, you son of a bitch? Pablo: ...Every fucking day of my life, brother.
Pablo's death. Played with as the show rightly points out how much suffering Escobar caused and juxtaposes his last moments with footage of the carnage from his bombing campaigns, but seeing Tata and Hermilda's breakdowns makes it brutal.
Season 3
Cordóva and his wife being killed by David, all the while Jorge is forced to watch.
Jorge having to betray Henrique - a man, who was always loyal to him and probably one of the nicer "villains" of season three - by framing him as a traitor to Miguel and David Rodriguez, in order to save his family from suffering the same fate Cordóva and his wife suffered from earlier the season.
Season 4
With Kiki still missing, Mika reads Charlotte's Web to their son. As she reads about Charlotte's death, she recognizes the parallels with Kiki and seems to realize, on some level, that he's not coming home.
"Nobody, of the hundreds of people that had visited the Fair, knew that a grey spider had played the most important part of all. No one was with her when she died."
Jaime's and Mika's reaction to the discovery of Kiki's body. Mika immediately knows when she opens the door for Jaime.
Season 5
The murders of Hector Palma‘s family. Not only is it gutwrenching to see two innocent children murdered as a cruel retaliation against their father, it also leads to Felix‘ ex-wife realizing just how much of a monster her former husband has become.
Season 6
Shortly after leaving jail, Amado learns that his daughter passed away while he was inside. After visiting her room, he takes one of her toy planes and holds on to it as a memento, and can be seen fondling it on several occasions.
Victor Tapia's entire story arc is one realistic tearjerker after another. He begins as a corrupt Juarez police officer who wants to be a good cop but finds himself constrained by his low income. After he stumbles upon the trail of a serial killer who murders women, Victor decides to finally be a real cop and turns to the DEA for help in exchange for informing on the cartel. Victor then loses his job and therefore has to do increasingly dirtier work for the cartel in order to make ends meet. After he finally catches up to the murderer and kills him, Victor discovers that it was not just one killer, but several who had been killing women all across Juarez, and so his entire crusade and all he did was for nought.
Even worse, the cartel eventually figures out he was the one informing on them, and have his best friend and former partner shoot him in the head. And unlike Walt and Andrea's story, there is no pay off. Victor's story ends no better than it began, with a good man who honestly wanted to do the right thing, and who ultimately paid the price for trying to do so.
Alex Hodoyan's fate. Despite all the bad he had done, it's hard not to feel sorry for him as it eventually becomes obvious that he's still just a kid dragged into a bad situation. After being tortured and manipulated for weeks, he runs away from Walt and the DEA to try and go home, but doesn't last two hours before the cartel finds him and hangs him from an overpass. His death is enough to bring Walt to tears, as it's implied he saw a lot of his own brother in Alex and therefore genuinely wanted to help him.
