CD1d is constitutively expressed in hematopoietic (macrophages, B cells, dendritic cells, innate lymphoid cells) as well as in non-hematopoietic cells (such as intestinal epithelial cells). While the role of CD1d in lipid presentation to NKT cells is well stablished, growing evidence supports additional “non-classical” roles for CD1d which impact the functions of CD1d-expressing cells. Our lab has recently identified a novel and unexpected function for CD1d as an immune-metabolic switch in macrophages. This function of CD1d is cell-intrinsic (and independent of NKT cells), and it controls lipid metabolic pathways and macrophage activation in vitro and in vivo. Moreover, the CD1d immune-metabolic axis is conserved between human and mouse and can be manipulated with an αCD1d antibody. In this talk, I will discuss the unconventional functions of CD1d, their effects in immune cell activation, the implications for disease and the opportunities for therapy.