Heat shock proteins (HSPs) play an important role in the maintenance of cellular homeostasis, particularly in response to stressful conditions that adversely affect normal cellular structure and function, such as hyperthermia. A remarkable intrinsic resistance of brain to hyperthermia reflects protection mediated by constitutive and induced expression of HSPs in both neurons and glia. Induced expression underlies the phenomenon of hyperthermic pre-reconditioning, where transient, low-intensity heating induces HSPs that protect brain from subsequent insult, reflecting the prolonged half-life of HSPs. The expression and activity of HSPs that is characteristic of nervous tissue plays a role not just in the maintenance and defense of cellular viability, but also in the preservation of neuron-specific luxury functions, particularly those that support synaptic activity. In response to hyperthermia, HSPs mediate preservation or rapid recovery of synaptic function up to the point where damage in other organ systems becomes evident and life threatening. Given the ability of HSPs to enhance gene expression by neurotropic viruses, the constitutive and inducible HSP expression profiles would seem to place nervous tissues at risk. However, we present evidence that the virus-HSP relationship can promote viral clearance in animals capable of mounting effective virus-specific cell-mediated immune responses, potentially reflecting HSP-dependent increases in viral antigenic burden, immune adjuvant effects and cross-presentation of viral antigen. Thus, the protective functions of HSPs span the well-characterized intracellular roles as chaperones to those that may directly or indirectly promote immune function.