MHC class II (MHC-II) molecules are best known for their function in antigen presentation – they promote T cell activation by displaying processed antigenic peptides on the surface of monocytes and other antigen-presenting cells. These cell surface molecules also have a lesser known signalling function, however, transmitting signals to tyrosine kinases and protein kinase C (PKC) that stimulate cell proliferation, cytokine release and apoptosis. Nuala Mooney and co-workers now delve further into MHC-II signalling (see p. 2565). They demonstrate that, in solid tumors expressing the MHC-II molecule I-Ak, engagement of I-Ak induces its recruitment to the detergent-insoluble glycolipid (DIG) fraction of the membrane – i.e. lipid rafts. The authors go on to show that PKCa is recruited to these rafts,and activated, when I-Ak is engaged. Furthermore, they show the disruption of the rafts by depletion of cholesterol blocks recruitment and activation of PKCa, as well as the actin rearrangements that occur during MHC-II signalling. These experiments thus reveal a critical role for lipid rafts in signalling by MHC-II molecules, placing recruitment of these molecules upstream of early signalling events such as PKC activation.