Potential applications of stem cells in medicine range from their inclusion in disease modeling and drug discovery to cell transplantation and regenerative therapies. However, before this promise can be realized several obstacles must be overcome, including the control of stem cell differentiation, allogeneic rejection and limited cell availability. This will require an improved understanding of the mechanisms that govern stem cell potential and the development of robust methods to efficiently control their fate. Recently, a number of small molecules have been identified that can be used both in vitro and in vivo as tools to expand stem cells, direct their differentiation, or reprogram somatic cells to a more naive state. These molecules have provided a wealth of insights into the signaling and epigenetic mechanisms that regulate stem cell biology, and are already beginning to contribute to the development of effective treatments for tissue repair and regeneration.