The critical role of peptide antigen-specific T cells in controlling mycobacterial infections is well documented in natural resistance and vaccine-induced immunity against Mycobacterium tuberculosis. However, many other populations of leukocytes contribute to innate and adaptive immunity against mycobacteria. Among these, non-conventional T cells recognizing lipid antigens presented by the CD1 antigen presentation system have attracted particular interest. In this chapter, we review the basic immunobiology and potential antimycobacterial properties of a subset of CD1-restricted T cells that have come to be known as Natural Killer T cells. This group of lipid reactive T cells is notable for its high level of conservation between humans and mice, thus enabling a wide range of highly informative studies in mouse models. As reviewed below, NKT cells appear to have subtle but potentially significant activities in the host response to mycobacteria. Importantly, they also provide a framework for investigations into other types of lipid antigen-specific T cells that may be more abundant in larger mammals such as humans.