The discovery that T cells recognize lipid and glycolipid molecules presented by CD1 proteins has greatly expanded the number of potential microbial antigens targeted by the immune system following infection. The ability of CD1d-restricted NKT cells to activate innate and adaptive immune responses has led to the idea that these cells can modulate immunity to infectious agents. In addition, CD1d-restricted NKT cells may directly contribute to host resistance as they express a variety of effector molecules that could mediate an antimicrobial effect. Although much has been learned about CD1d-restricted NKT cells through the use of the synthetic antigen α-galactosylceramide (αGalCer), the field has been hampered by the paucity of information about the physiological self and microbial lipid antigens that can be presented by CD1d. Here we review the literature stating that CD1d-restricted NKT cells contribute to host defense against microbial pathogens.