Mycobacteria are unique in that their thick cell wall contains a variety of lipid and glycolipid components that are critical for survival and virulence of the microbes. Studies over the past decade have established that our immune system has evolved an outstanding ability to elicit immune responses directed specifically against these highly hydrophorbic lipid antigens. Unlike MHC molecules that bind peptide antigens, human group 1 CD1 molecules (CD1a, CD1b, CD1c) bind mycobacteria-derived lipid antigens and present them to specific T cells that control mycobacterial infection. Presensitization of these CD1-restricted T cells with specific lipids results in protection against tuberculosis, underscoring the possibility that lipids may comprise a new biochemical class of vaccines against microbial infection. Further, the humoral immunity against certain glycolipids derived from the cell wall of mycobacteria has also been noted in patients with active tuberculosis, and the IgG antibody titers correlate with the disease activity. Thus, these lipid-specific immune responses have significant medical implications that have never been recognized previously.