Although stem cells hold considerable promise for the treatment of numerous diseases including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes and cancer, obstacles such as the control of stem cell fate, allogenic rejection and limited cell availability must be overcome before their therapeutic potential can be realized. This requires an improved understanding of the signaling pathways that affect stem cell fate. Cell-based phenotypic and pathway-specific screens of natural products and synthetic compounds have recently provided a number of small molecules that can be used to selectively control stem cell proliferation and differentiation. Examples include the selective induction of neurogenesis and cardiomyogenesis in murine embryonic stem cells, osteogenesis in mesenchymal stem cells and dedifferentiation in skeletal muscle cells. Such molecules will likely provide new insights into stem cell biology, and may ultimately contribute to effective medicines for tissue repair and regeneration.