The heat shock response was originally characterized as the induction of a set of major heat shock proteins encoded by heat shock genes. Because heat shock proteins act as molecular chaperones that facilitate protein folding and suppress protein aggregation, this response plays a major role in maintaining protein homeostasis. The heat shock response is regulated mainly at the level of transcription by heat shock factors (HSFs) in eukaryotes. HSF1 is a master regulator of the heat shock genes in mammalian cells, as is HSF3 in avian cells. HSFs play a significant role in suppressing protein misfolding in cells and in ameliorating the progression of Caenorhabditis elegans, Drosophila and mouse models of protein-misfolding disorders, by inducing the expression of heat shock genes. Recently, numerous HSF target genes were identified, such as the classical heat shock genes and other heat-inducible genes, called nonclassical heat shock genes in this study. Importance of the expression of the nonclassical heat shock genes was evidenced by the fact that mouse HSF3 and chicken HSF1 play a substantial role in the protection of cells from heat shock without inducing classical heat shock genes. Furthermore, HSF2 and HSF4, as well as HSF1, shown to have roles in development, were also revealed to be necessary for the expression of certain nonclassical heat shock genes. Thus, the heat shock response regulated by the HSF family should consist of the induction of classical as well as of nonclassical heat shock genes, both of which might be required to maintain protein homeostasis.