Tuberculosis is an ancient disease, known to affect particularly the poor and most vulnerable populations. Since the beginning of time, the disease claimed more lives than any other infectious disease. This is a curable disease with treatments available and a centenary vaccine, Bacillus Calmette-Guérin (BCG), that provides some protection to infants but loses efficacy in adolescents and adults. More than one million people still succumb to the disease every year. In the last two decades, dozens of new vaccine candidates have emerged, bringing hope to defeat the pathogen. Now is the time to look in detail at the vaccines under development and understand how they can contribute to reduce the global burden of tuberculosis. But to do that, we must understand the peculiar nature of the etiologic agent of this disease. Tuberculosis is caused by a persistent, clever, and manipulative pathogen, the Mycobacterium tuberculosis that has been studied for centuries, and puzzled generations of scientists. In this chapter, the history, biology, and physiology of the pathogen are introduced to characterize the organism and the host response. Only with the profound knowledge of the biology of the pathogen we will be able to develop weapons to defeat it.