Leprosy is a bacterial infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis. It has a very long history and continues to challenge people and healthcare providers today in specific regions of the world. Affecting primarily the skin, peripheral nerves and other body tissues such as the skeleton, the disease is rapidly declining as a result of education, chemotherapy and other interventions. The Global Leprosy Strategy 2016‒2020 further aims to contribute to a leprosy-free world. Leprosy’s deep history has been documented in historical writings, artwork and in human remains from archaeological sites globally. In recent decades modern and ancient genetic analyses have contributed more to our understanding of the origin and evolution of the causative bacteria and the human immune response. In considering evidence from medicine, genetics, archaeology and history, this chapter provides insight to the evolution of this disease that continues to spark interest from both academics and the public.