Tuberculosis (TB) is a bacterial infectious disease caused by organisms from the Mycobacterium tuberculosis complex, Mycobacterium tuberculosis and Mycobacterium bovis being of most importance to humans. TB is one of the top ten causes of death globally and the leading cause from a single infectious agent (higher than HIV infection). Classed as a re-emerging infectious disease and a disease of poverty, it has been estimated that 10 million people fell ill with TB in 2019, and there were 1.2 million deaths. Around one-quarter of the population of the world has latent TB and 5–15% of these people will go on to become ill with the disease. Even though TB is curable, drug resistance is a particular challenge in treatment regimens. In 2014 and again in 2018, the World Health Organization’s The End TB Strategy was approved by the World Health Assembly, with the goal of ending the TB epidemic by 2030 (World Health Organization, 2014). TB affects the lungs, gut and other organs of the body, including the skeleton. Its deep history has been documented globally in historical writings, artwork and in human remains from archaeological sites globally, and in recent decades modern and ancient genetic research has contributed more to our understanding of the origin and evolution of the causative bacteria. In considering evidence from medicine, genetics, archaeology and history, this chapter provides insight to the evolution of this pathogen that continues to challenge the world’s knowledge base and resources.