Heat shock factor Hsf in nonvertebrate animals and homologous heat shock factor Hsf1 in vertebrate animals are key transcriptional regulators of the stress protein response. Hsf/Hsf1 is constitutively present in cells but is, typically, only active during periods during which cells are experiencing a physical or chemical proteotoxic stress. It has become increasingly clear that regulation of Hsf/Hsf1 activity occurs at multiple levels: the oligomeric status of Hsf/Hsf1, its DNA-binding ability, posttranslational modification, transcriptional competence, nuclear/ subnuclear localization, as well as its interactions with regulatory cofactors or other transcription factors all appear to be carefully controlled. This review emphasizes work reported over the past several years suggesting that regulation at several of these levels is mediated by repressive interactions of Hsp90-containing multichaperone complexes and/or individual chaperones and Hsf/Hsf1.