- "Josh is Done". Even sadder after the drama that ensued years later when, in real life, Drake didn't receive an invitation to Josh's wedding, essentially inverting the episode's premise (they patched things up later, however).
Drake: I need you more than you need me! I need you WAY more than you need me! I'm sorry I made you late for your exam! I'm sorry I ran over your bike! I'm sorry I'm probably the worst brother in the world, and you're way better off without me! I just need you to understand...(stammers) Sorry, Josh. I'm sorry. (leaves)
- Drake's breakdown when his life falls apart without Josh leading to an embarrassing incident in the science room.
- Josh's "The Reason You Suck" Speech to Drake in "Dune Buggy" about how Josh Can't Get Away with Nuthin' while Drake gets him into trouble for everything. Like the above scene, it's one of the few moments in the show that's played completely serious.
- Josh's reaction when he thinks his father is cheating.
- Drake and Josh's letter from the Christmas Special.
- Wendy's broken heart after Drake yells at her in "#1 Fan."
- Megan's broken heart when her boyfriend breaks up with her before her brothers reveal he was cheating on her. It's one of the few times we see a sad side to Megan, who after dumping her cheating boyfriend, approaches her brothers and quietly asks them to take her home.
- Depending on how sympathetic you are to her at this point, Megan being ostracized by her classmates (even being uninvited to a birthday party) because of Josh being her class's student teacher.
- The house that the show took place in was recently demolished.
- The ending of "Mindy Loves Josh", Mindy breaks up with Josh, simply because Josh couldn't say the same back and thanks to Drake terrifying him over the idea of a former school rival saying "I love you".
Tear Jerker / Drake & Josh