Natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens in the context of the MHC class I-related glycoprotein CD1d. Recent studies have identified multiple ways in which NKT cells can become activated during microbial infection. Mechanisms of CD1d-restricted antigen presentation are being unraveled, and a surprising connection has been made to proteins that control lipid metabolism and atherosclerosis. It appears that several microorganisms have developed strategies to interfere with the CD1d antigen-presentation pathway. New studies have also provided important insight into the mechanisms that control effector cell differentiation of NKT cells and have revealed specialized functions of distinct NKT cell subsets. Finally, there is continued enthusiasm for the development of NKT cell-based therapies of human diseases.