Kill 100 creatures with the glove of Azoth. You will obtain this weapon in Act 4, just after you climb the tower and fight the transformed puppet survivors.
Use the glove by pointing your left arm up, and touching your right hand to your left elbow. You can charge up the weapon by holding this pose for a few seconds. Fire by thrusting your left palm outward. Charged shots can take out small groups of enemies.
Your kill counts carry over from each playthrough, so this will eventually unlock this as long as you use this weapon to make kills.