Kind of a Fridge Tearjerker, the scene early on where Tenma overhears Harima's story about rescuing her from hoodlums and botching his attempted Rescue Romance. Tenma, having no memory of the incident (or at least not enough to connect the dots), reassures him that it was all the girl's fault. As funny as the scene is it at first, it does leave you wondering whether Tenma had regretted rejecting him the way she did.
When Mikoto reunites with the senpai she's been crushing on - only to also meet his girlfriend, whom she wasn't aware of. She laughs off her disappointment and acts like her usual self.
Parodied when Madoka, Shigeo and Mai shoot each other to the tune of "Feel Like A Girl". Then again, they were just playing...
A flashback showing that as young children Yakumo was not at all fond of Tenma, whom constantly ruined anything she was working on. What made her angry the most was Tenma accidentally ruining the book Yakumo loved because their dad gave to her and would read it. She shut Tenma completely off which obviously stressed the latter.
Chapter 195: Mikoto revealing she and and Asou broke up for reasons mostly unknown. It seems mutual and not too extreme especially on Mikoto's side, until they run into each other the next day are obviously feel uncomfortable about it... and then you later see Asou tell Suga, "I loved her. I really did."
Made worse in the flat chapter (b44) in that volume where it focuses on Mikoto pre-breakup contemplating whether to tell Asou she loves him or not, worrying that the relationship won't go anywhere if she doesn't. She finally decides to confess to him and the chapter ends with her feeling confident about it while leaving for their date - the date where they broke up.
Eri and Yakumo's friendship falling apart after Eri started to ostracize Tenma whom she thought had feelings for Harima.
Chapters 273 of the manga. Not to mention the chapter RIGHT AFTER that, where Tenma comes to see Karasuma and he lost all memories of her, while she tearfully recounts all the good times they had during school. Absolute heartbreak, especially when Tenma starts to cry.