The present invention provides methods, media and compositions capable of modulating the differentiation of stem cells. Applicants have discovered that agonists of lysophospholipid receptors and ligands of class III tyrosine kinase receptors are useful in preventing the spontaneous differentiation of stem cells. The ligands and agonists may be used alone, or in combination where they have a synergistic effect. Also provided are cells produced using the methods and media, and methods of treating stem cell related diseases using the compositions described herein. Methods of identifying compounds useful in finding other agents useful in the modulation of stem cell differentiation are also disclosed.