The heat shock response is an ancient and highly conserved process that is essential for surviving environmental stresses, including extremes of temperature. Fever is a more recently evolved response, during which organisms temporarily subject themselves to thermal stress in the face of infections. We review studies showing that fever is beneficial in the infected host. We show that core temperatures achieved during fever can activate the heat shock response and discuss some of the biochemical consequences of such an effect. We present data suggesting 4 possible mechanisms by which fever might confer protection: (1) directly killing or inhibiting growth of pathogens; (2) inducing cytoprotective heat shock proteins (Hsps) in host cells; (3) inducing expression of pathogen Hsps, an activator of host defenses; and (4) modifying and orchestrating host defenses. Two of these mechanisms directly involve the heat shock response. We describe how heat shock factor-1, the predominant heat-induced transcriptional enhancer not only activates transcription of Hsps but also regulates expression of pivotal cytokines and early response genes. The relationship between fever and the heat shock response is an illuminating example of how a more recently evolved response might exploit preexisting biochemical pathways for a new function.