When approaching Vampire, many readers are confused by the fact that it seems to be about werewolves. The story begins in a village of vampires who are destroying their homes setting out into the world because humans are moving into their valley, but these "vampires" do not drink blood, nor are they immortal. Instead they all transform into animals, ranging from wolves and bats to snakes and crocodiles, the transformations being triggered by different stimuli for each vampire. For example, the main vampire, Toppei, turns into a wolf when he sees the moon or when he is scared. His little brother Chippei transforms whenever he sees anything round. Others transform at the smell of onions, the sight of a telephone pole, or a variety of other stimuli.
Vampire marked a major turning point in Tezuka's life, at which he began to pay more attention to the darker side of the human psyche, characterized by darker, less heroic protagonists and more complicated villains.