The resurgence of tuberculosis worldwide has intensified research efforts directed at examining the host defense and pathogenic mechanisms operative in Mycobacterium tuberculosis infection. This review summarizes our current understanding of the host immune response, with emphasis on the roles of macrophages, T cells, and the cytokine/chemokine network in engendering protective immunity. Specifically, we summarize studies addressing the ability of the organism to survive within macrophages by controlling phagolysosome fusion. The recent studies on Toll-like receptors and the impact on the innate response to M. tuberculosis are discussed. We also focus on the induction, specificity, and effector functions of CD4(+) and CD8(+) T cells, and the roles of cytokines and chemokines in the induction and effector functions of the immune response. Presentation of mycobacterial antigens by MHC class I, class II, and CD1 as well as the implications of these molecules sampling various compartments of the cell for presentation to T cells are discussed. Increased attention to this disease and the integration of animal models and human studies have afforded us a greater understanding of tuberculosis and the steps necessary to combat this infection. The pace of this research must be maintained if we are to realize an effective vaccine in the next decades.