Recent studies of CD1 structure and intracellular trafficking have demonstrated significant differences among the CD1 isoforms (CD1a, CD1b, CD1c and CD1d). The molecular and structural basis for the differential trafficking of CD1 molecules has also been delineated. These observations broaden our understanding of why the immune system has evolved multiple CD1 isoforms to survey different cellular compartments for lipid antigen presentation, to provide host defense against the microbial world and to offer immunoregulation with relevance to tumor immunity and autoimmunity.