Over the last decade, human stem cells have received much attention in the scientific, as well as in the political arena. Based on their fundamental properties of self-renewal and pluripotency, these cells are anticipated to contribute to further our understanding of human development and the causes of congenital birth defects. In addition, human stem cells are beginning to find a practical use in new and improved models for drug discovery, and in the future, these cells may also potentially be used for the treatment of severe human diseases. In order to realize the great promise of human stem cells, there is a need for highly selective and efficient methods for maintenance and differentiation of the cells to produce large quantities of undifferentiated cells or populations of particular cell types. Currently, most protocols for stem cell expansion and differentiation involve poorly defined mixtures of protein growth factors and signaling molecules alone, or in combination with cellular genetic manipulations. In addition, the exploitation of specific low molecular weight compounds has proven successful for affecting basic stem cell properties such as proliferation, self-renewal, and differentiation. In the present review, we discuss some of the opportunities of modulating the state of human embryonic stem (hES) cells by exogenous synthetic substances. We also highlight some strategies for the identification of novel low molecular weight compounds capable of altering the hES cell fate. The access to inexpensive and specific tools for in vitro hES cell manipulations will be critical for realizing the industrial and medical applications of these cells.