The Variola virus is the causative agent of smallpox—a simple yet deadly single-stranded DNA virus that is part of the family Poxviridae and has been a menace of the Earth since before recorded history, dating back to about 10 000 bc. Smallpox has continued to play an intimate role in shaping human society, from ancient times as a plague of the world to modern times where the threat of smallpox use in bioterrorism looms. Variola primarily attacks the skin, leading to an impressive characteristic maculopapular eruption that can encompass the entire body and leading to a presumptive clinical diagnosis. Thus, it was once the deadliest dermatological ailment. Let us take a journey through time and explore how this virus has shaped human history and culture.