Treatment of leprosy with a sulfone, reported in 1944, was one of the earliest uses of antimicrobials to treat bacterial infections in man. The description of leprosy that comprises Chapter 13 of Leviticus in the Bible dates back some 3400 years, making it one of the earliest written records of a specific disease. Gerhard Henrik Armauer Hansen’s discovery of the leprosy bacillus in 1873 was perhaps the first identification of a pathogenic bacterium. The stage is set by analyzing the concept of macrophage activation and summarizing the features of lepromatous leprosy that beckoned as a setting in which to test these concepts. “Macrophage activation” refers here to an induced increase in the capacity of the macrophage to kill or inhibit microbes in defense of the host. While the ability of macrophages to kill the agents of non-opportunistic infections is constitutive, the ability to kill many opportunistic microorganisms is inducible.