Throughout our history, humans have suffered catastrophic numbers of deaths due to infectious diseases. Here are nine of the deadliest and most widespread epidemics of all time.

Smallpox

Emerging in human populations around 10,000 B.C., smallpox eventually killed between 300 and 500 million people worldwide, during the 20th century alone. After vaccination programs, smallpox was eradicated by 1979 and is credited for creating the medical science of vaccination.

Influenza

The first recorded influenza (flu) outbreak was in 1850. The most famous and lethal outbreak was the 1918 Spanish flu pandemic, which lasted from 1918 to 1919 and killed between 50 to 100 million people. The disease likely influenced the course of World War I by sickening and killing soldiers. Outbreaks still occur every year, resulting in three to five million cases and about 250,000 to 500,000 deaths worldwide.

Rabies

One of the oldest infectious diseases, rabies was first recorded around 2,000 B.C. It is a viral disease, caused when an infected animal scratches or bites another animal or human. It still occurs today, with nearly 24,000 to 60,000 deaths worldwide per year.

Tuberculosis

Tuberculosis has been present since ancient times and found in prehistoric humans dating as far back as 4000 B.C. In 2014 alone, there were 1.5 million recorded tuberculosis-related deaths worldwide. TB is caused by a bacteria and generally affects the lungs, but can also affect other parts of the body. Some estimates say that nearly one-third of the world’s population is believed to be infected with some form of TB. Many famous people have been afflicted with tuberculosis, including Edgar Allen Poe and Eleanor Roosevelt. The battle against tuberculosis stimulated some of the first efforts to develop antibiotics.

Leprosy

The oldest documented evidence for leprosy has been traced to 2000 B.C. In the 1980s, there were nearly 5.2 million cases worldwide. Leprosy rates have declined and cases are rare. In 2015, 178 cases were reported in the U.S. Leprosy can easily and effectively be treated with standard antibiotics.

Typhoid Fever

Also known as typhoid fever, typhoid is a bacterial infection that affects over ten million people every year with over 200,000 related deaths worldwide. Typhoid is spread via contaminated food and water. Typhoid plagues have been documented throughout history and during the American Civil War. Nearly 80,000 Union soldiers died of typhoid. Approximately 300 people are infected with Typhoid each year in the U.S. Many historians believe Alexander the Great perished from typhoid fever.

Bubonic and Pneumonic Plagues

Perhaps the most notorious of all infectious diseases, the bubonic and pneumonic plagues are believed to be the cause of the Black Death that rampaged through Asia, Europe and Africa in the 14th century killing an estimated 50 million people. The plague is still present today, however it is a much different disease now and spreads much, much slower than in the past. In the U.S., there are about seven reported cases each year. The concept of quarantine, isolating infected people as a way to stop the spread of disease, was developed in Europe in response to the plague.

Malaria

Malaria is a mosquito-borne infectious disease. Instances of malaria are found throughout recorded history. The disease is still widespread in tropical and subtropical regions around the world. Every year nearly 200 million people are affected by malaria, with hundreds of thousands dying from the disease.

HIV/AIDS

Classified as a global pandemic, HIV/AIDS led to nearly 30 million deaths worldwide from 1980 to 2009. In 2015, 2.1 million new cases were reported worldwide. The disease still kills roughly one million people per year worldwide, down from a peak of 2.2 million in 2005.