Natural Killer T (NKT) cells constitute a conserved T lymphocyte sublineage that has been implicated in the regulation of various immune responses, including the responses to viruses, bacteria, and parasites. NKT cells recognize self and foreign glycolipids presented by CD1d, a non-classical antigen-presenting molecule, and they rapidly produce various cytokines. Many studies have shown that NKT cells have protective roles following microbial infection through the amplification of innate and adaptive immunity, although NKT cells have detrimental roles in some cases. Recent studies have shed light on the natural antigens recognized by NKT cells and the mechanisms whereby they contribute to host defense, and they suggest that these unique T cells have evolved to jump start the immune response to microbes.