Many differentiation programs are accompanied by an increase in small heat shock proteins (sHsps) level. Most of the time transient, this accumulation takes place during the early phase of the process and is correlated with the growth arrest that precedes the differentiation. Important biochemical modifications of sHsps occur, such as changes in phosphorylation and oligomerization. The fact that these proteins are induced independently of the signal that triggers differentiation, of the differentiation type, and of the cell type strongly suggests their involvement in fundamental mechanisms of cellular differentiation. Moreover, impairment of sHsps accumulation leads to abortion of the differentiation program and, subsequently, to a massive commitment to cell death. Recent advances in this field of research are presented as well as the hypothesis that should be tested to unravel the mode of action of these proteins during cellular differentiation. © 2004 Wiley‐Liss, Inc.