Human pluripotent stem cells provide unlimited starting material to generate differentiated cells that can be used to build a functional organ. Essential to this pursuit is an efficient way to differentiate pluripotent stem cells into specific types of mature cells. Cell-permeable small molecules that can modulate the function of specific proteins provide a convenient and efficient approach to controlling stem/progenitor cell fate. Our laboratory has an in house chemical library containing 6,000 chemicals, including kinase inhibitors, signaling pathway regulators, nature products and FDA-approved drugs, and protein library containing 400 growth factors. In addition, we have access to multiple chemical libraries containing at least 165,000 compounds from the high-throughput screening resource center at Rockefeller University. Using high content and high throughput screening approaches, we have identified a series of small molecules that control stem cell self-renewal, differentiation and reprogramming. We are currently focusing on the identification of the small molecules that direct human pluripotent stem cells differentiation into certain cell types, including pancreatic endocrine cells, exocrine cells, hepatocytes, cardiomyocytes and pacemaker cells.