MORGANNA MODE GONE: As a fan of .hack, this is a bit obligatory. Morganna is an interesting play on the Insane AI cliche. Her goal is to basically axe off her daughter AI, Aura, so she can basically keep being the head honcho of the ingame MMO, The World. And then she starts to branch off, creating 8 figments of herself, the 8 Phases, to basically send The World AND the actual real world into panic. Also, her voice in SIGN is simply sinister.
Relius Clover and Ghetsis: I put them both here because not only are they very similar in appearance, they also have similar moral standpoints. Ghetsis wants to take over the world, using N using Reshiram/Zekrom. He is implied to have completely sheltered N just to achieve this desire, and is even implied to have killed N's original father, and capture it's spirit. (Think about it. N has no known parents, and Ghetsis has a Conhagrigous, which evolves from a Pokemon that come from dead people...) As for Relius? This guy is even worse! He took his own wife and turned her into a puppet to follow his commands! I won't spoil much else, but if you get Makoto's bad ending... You'll see just how despicable he is.