When Ted gives Michael a speech not to chase the idea of Brian but notice the one who is already pining for him. So Michael moves in with David.
The bombing at Babylon provokes quite a few of these moments. Between Brian calling frantically for Justin and then Michael in the blasted building, or demanding a nurse at the hospital accept his blood for Michael's transfusions, there are no shortage of painful moments.
After Brian and Justin call off the wedding and the latter decides to move to New York the two make love for the final time in the series while a montage of their previous encounters flickers across the screen. The real tearjerker comes when the camera focuses on them in bed and Justin slowly fades from the scene, emphasizing his absence after fighting so hard for them to be together.
Vic's death in Season Four, and Brian, Michael, and Debbie's reactions to it.