Heat shock transcription factors (HSFs) are widely known as master regulators of the heat shock response. In invertebrates, a single heat shock factor, HSF1, is responsible for the maintenance of protein homeostasis. In vertebrates, seven members of the HSF family have been identified, namely HSF1, HSF2, HSF3, HSF4, HSF5, HSFX, and HSFY, of which HSF1 and HSF2 are clearly associated with heat shock response, while HSF4 is involved in development. Other members of the family have not yet been studied as extensively. Besides their role in cellular proteostasis, HSFs influence a plethora of biological processes such as aging, development, cell proliferation, and cell differentiation, and they are implicated in several pathologies such as neurodegeneration and cancer. This is achieved by regulating the expression of a great variety of genes including chaperones. Here, we review our current knowledge on the function of HSF family members and important aspects that made possible the functional diversification of HSFs.