Bowser: Not only is he the best villain ever, but also the most successful VG character ever, according to Cracked.com.
GLaDOS: That eerie voice, the way she tortures subjects, and her insults to Chell.
Marx: He's that type of villain no one expects, and he still fits within the Kirby universe unlike most final bosses. As for his Soul version, that ear rape voice. O_o
M. Bison: For you, being a leader of Shadaloo, a wielder of psycho powers, and a murderer would make the purpose of beating him the most important thing in your life, but for him, it was Tuesday.
Dr. Eggman: You just gotta love his stache and his machines, including his mooks from various incarnations (and Metal Sonic).
Master Xehanort: This guy is a true mastermind, as every event that has happened throughout the Kingdom Hearts series is all part of his plan to revive the X-Blade and start another keyblade war for science.
Ganondorf: As a reincarnated version of Demise's hatred, Ganondorf will always be bad to the bone, and no matter how many times he's imprisoned, he'll always come back, though Twilight Princess is a strange case, as he actually died in that game, so maybe the next Zelda game should take place between TP and Four Swords Adventure regarding ressurecting Ganon for timeline continuity's sake and how reincarnations work in general that contradict FSA being after TP.
Dr. Wily: He's made some of the best robot masters in the series, including Air Man, who can't be defeated even with the Leaf Shield, and his machines are harder to beat than Eggman's if you don't know which weapn they're weak against.