These are what we call the 'YMMV items.' Things that some people find in this work. We call them 'your mileage might vary' because not everyone sees these things in the same way. This starts discussions in the trope lists, a thing we don't want. Please use the discussion page if you'd like to discuss any of these items.
Tear Jerker: Quite a few. Collin's conversation with his mother shortly after she finds proof that he's Fox's boyfriend; Collin's painkiller-induced confession that he doesn't like Fox paying attention to girls (and Fox's reaction); Bootsie/Anne's farewell to Collin and, conversely, her humiliating departure from her apartment in Chicago.
Broken Base: Given the fandom's amiable nature, it's not a true, cat-fighting broken base...but the FH/OPB transition split the group into distinct Fox/Collin and Leon/Collin factions.
Family-Unfriendly Aesop: Depending on how cynical you feel, you could compare the fates of Rudd and Fox and draw the conclusion that "jerks get happy endings, nice guys are less fortunate." Fatima's seemingly successful, out-of-nowhere marriage (her husband didn't know her name until she signed the register), contrasted with her brother's relationship, could be read as "relationships with a solid basis in friendship and communication are less likely to succeed than those conducted through lust and/or on a whim." Or you could accept the more sympathetic, but still family-unfriendly aesop: "Sometimes, with the best will in the world and all the right ingredients, a relationship will fail because people change."
Fanon Discontinuity: A rare example of the author advocating this. In the commentary to the final comic, she lists three possible outcomes for Fox and Collin. After stating that she already knows which one she is going to stick with, she reassured the audience that if they didn't like that, that's not the ending they had to go with. Which was correctly interpreted as proof that Fox and Collin's relationship went down the drains inbetween FH and OPB..
"Funny Aneurysm" Moment: When Derringer is first introduced, Fox wants nothing to do with him, and is quick to stress that Collin is his "best friend." Fast forward to the comic's end, and Fox comments that Derringer is now his best friend.
This can even make the happiest and most romantic scenes sad if you read the sequel comic: At the end of the Pirates storyline, Collin and Fox are overjoyed to be reunited and are kissing - the last time the reader will see them do so - and making doe eyes at each other while Rudd, Kitty and Derringer carry on a conversation behind them. Rudd remarks that Collin reminds him of a Bond villain - all he needs is the cat. By O.P.B, Collin has acquired both the status and the cat, at Fox's expense.
Informed Wrongness: Fox is freaked out about Collin's Creed job and is even suspicious of his new company car. Fans, the plot and characters alike treated him as if he was being ridiculous. Other People's Business shows that he wasn't completely off target.
The Woobie: Fans were split on whether Fox or Collin was the Woobie for this time period - often it depends on who you blame for the relationship problems.
OPB spoiler: In the canon, given that Collin is now perfectly happy while Fox's life fell apart, it looks like Fox wins the woobie stakes.