The series takes place in an indeterminate time in the future, 500 years after an apocalyptic war between all of Earth's nations destroyed civilization, when humanity has reestablished itself. In this future world, the Roman Catholic Church has become a major military power, whose goals include the protection of humanity against the vampiric Methuselahs, who war upon humankind (or "Terrans," as they call humans). The seat of power is the Vatican, an attractive place with traditional European architecture; it is likely the same Vatican city in the real world (albeit perhaps rebuilt following the previous war). The Methuselahs are themselves another major political and military force. Their capital of Byzantium (presumably built on the site of the real world's Byzantium, now Istanbul) appears as an elegant metropolis, surrounded by a field of particles which filters out UV radiation, thus protecting the Methuselah population.

Both sides in this conflict are in a barely-contained cold war against each other. The current countries use "lost technologies," remnants of advanced technology that survived the apocalyptic war. These include airships, missiles, computers, etc. Worth noting is a third great power, Albion; it is a future version of Britain, with Buckingham Palace clearly seen in a number of episodes, reigned over by a monarchy. It is characterized by its superior arsenal of lost technology and weapons, and a higher level of manufacturing ability than the Vatican. Other states are rarely mentioned, but the novelized/manga version does refer to the existence of such countries.