A joke that forced me to actually pause the game while I laughed my ass off for over a full minute, "Fission Mailed" was definitely the comedic high point of the surprisingly funny PS2 game "Metal Gear Solid 2: Sons of Liberty".
Toward the end of the game, the game interface (the pause screen, radar box, codec/dialogue box) goes completely haywire for very long and involved spoiler-ish reasons that won't be discussed here. This bizarre sequence includes the pause screen generating random location names for the rooms you're in, the radar screen being replaced with a video of an Asian model, some characters either tripping out or becoming violently psychotic, and the game world generally acting screwy. Many of these things caused me and several other PS2 gamers across the world to laugh out loud, but the very best and definitely the most popular joke among the fans had to be "Fission Mailed", a sequence where the game over music and screen pops up out of nowhere in the middle of playing, but with the usual big, bold text reading "MISSION FAILED" replaced with "FISSION MAILED", and the "Continue/Exit" option replaced with "EMIT/CONTINENT".
Aside from the laugh factor, this joke also has to be admired for its boldness. This joke suddenly appears during the middle of a very dramatic scene where the hero, armed with a new bad-ass weapon that Metal Gear fans have been clamoring for since Metal Gear Solid debuted four years ago on the PlayStation, fights alongside his (as well as every Metal Gear player's for the last decade) hero, Solid Snake, in a fight against a huge horde of very cool-looking, katana-wielding enemies. Had this joke done any less than sent the players to the floor laughing hysterically, it would have been widely thought of as a disgusting eyesore that ruined the dramatic high point of the game's very deep and emotional story. It was a huge gamble on the part of the creators, and it worked perfectly.