The members of the small heat shock protein (sHSP) family are molecular chaperones that play major roles in development, stress responses, and diseases, and have been envisioned as targets for therapy, particularly in cancer. The molecular mechanisms that regulate their transcription, in normal, stress, or pathological conditions, are characterized by extreme complexity and subtlety. Although historically linked to the heat shock transcription factors (HSFs), the stress-induced or developmental expression of the diverse members, including HSPB1/Hsp27/Hsp25, αA-crystallin/HSPB4, and αB-crystallin/HSPB5, relies on the combinatory effects of many transcription factors. Coupled with remarkably different cis-element architectures in the sHsp regulatory regions, they confer to each member its developmental expression or stress-inducibility. For example, multiple regulatory pathways coordinate the spatio-temporal expression of mouse αA-, αB-crystallin, and Hsp25 genes during lens development, through the action of master genes, like the large Maf family proteins and Pax6, but also HSF4. The inducibility of Hsp27 and αB-crystallin transcription by various stresses is exerted by HSF-dependent mechanisms, by which concomitant induction of Hsp27 and αB-crystallin expression is observed. In contrast, HSF-independent pathways can lead to αB-crystallin expression, but not to Hsp27 induction. Not surprisingly, deregulation of the expression of sHSP is associated with various pathologies, including cancer, neurodegenerative, or cardiac diseases. However, many questions remain to be addressed, and further elucidation of the developmental mechanisms of sHsp gene transcription might help to unravel the tissue- and stage-specific functions of this fascinating class of proteins, which might prove to be crucial for future therapeutic strategies. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.