Recent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases. For better understanding of the molecular mechanisms that control stem cell fates as well as an improved ability to manipulate these cells, we have developed and implemented chemical and functional genomic tools, including high throughput cell-based phenotypic screens of arrayed chemical, cDNA and RNAi libraries, and performed genomic and proteomic profiling of homogenous undifferentiated/self-renewing or selectively differentiated cell populations under chemically defined conditions. In-depth biochemical and functional assays in vitro and in vivo, have been applied to identify and further characterize small molecules and genes that can control stem cell fate in various systems.