Ra's Al Ghul
Real Name: Unknown
First Appearance: Batman #232
Insane Twist: Believes the only way to save the world is the kill off the majority of humanity and start fresh.
Crowning Moment: After a long courtship, Batman marries Talia Al Ghul and becomes Ra's heir in Son of the Demon. Not only does the Demon's Head gain a son, but Wayne joins his army and even sires a child with Talia.
Ra's is Batman's mental equal, financial superior and surrogate father (though long removed). Sure, Ra's may be "dead" right now, but it won't last -- it never does. Ra's is the only regular Batman villain who threatens the world on a global scale. He and Batman have a deep personal history and are more like family than anything else. Ra's earns Batman's attention quicker than any other, because he is such a threat, but being temporarily deceased has dropped Ra's from the #1 spot for now.
Bane
Real Name: Unknown
First Appearance: Batman: Vengeance of Bane #1
Insane Twist: Formerly addicted to the super-steroid Venom, Bane is now merely consumed with gaining power in the world.
Crowning Moment: Breaking Batman's spirit and then breaking his back.
Bane could easily have been #1 on the list, but since his brilliant show of destroying Batman, Bane has turned into a worthless Neanderthal. During "Knightfall" Bane didn't just break Batman's back, he broke Batman's will. While most villains choose chaotic strategies to take out Batman, Bane's plan was simply to unleash ever whacko from Arkham, run Batman ragged, and then face the Dark Knight when he had nothing left. Batman barely had the will to go on living after his battle with Bane. Too bad the past few years have negated Bane to a rather simple thug.