Mycobacterium tuberculosis has been identified in prehistoric remains of humans. Despite references to TB by Hippocrates and Galen, humankind had limited understanding of and few tools to defend itself against TB until the later 19th century. Subsequently, landmark advances in the 20th century provided the means to control and prevent this disease. At the same time, epidemiological developments and fundamental problems related to human behavior, socioeconomic conditions, and political circumstances continue to thwart efforts to diminish the burden of suffering and death caused by TB. This article reviewed some of these issues including the global failure of TB control in the late 20th century, the worldwide emergence of drug-resistant TB, the extensive spread of HIV infection and its impact on TB incidence; and changing health care and political environments. The obstacles to TB control remain and will remain challenges in the coming years. Still, recent developments in immunology, biochemistry, and molecular biology suggest that new knowledge and tools are just around the corner. These will enhance the ability to conquer this microbe by the end of the current century.