Heat shock proteins (HSPs) are recognized for their support of protein metabolism. Interaction with viral proteins also enhances the development of innate and adaptive immune responses against the infecting agent. At the level of the infected cell, HSPs are uniquely expressed on the cell surface, where they represent targets of lymphokine activated killer cells. Necrosis of the infected cell releases complexes of HSP and viral protein, which, in turn, binds antigen-presenting cells (APCs). One effect of binding is to stimulate APC maturation and the release of proinflammatory cytokines, an adjuvant effect that prepares the way for adaptive immune responses. A second effect of binding is to direct the antigenic cargo of the HSP into endogenous MHC presentation pathways for priming of naive cytotoxic T cells (CTL) or activation of antigen-specific CTLs. This alternate pathway of antigen presentation is essential to CTL priming following primary brain infection. Using heat shock to elevate brain levels of HSP in a mouse model of measles virus (MV) persistent infection, we provide evidence supporting a role for HSPs in promoting cell-mediated viral clearance from brain. The findings highlight the probable relevance of HSPs to anti-MV immunity, suggesting novel routes of both therapeutic intervention and preventative measures.