The use of small specific molecules has been instrumental in the modulation of stem cell proliferation and differentiation to obtain insulin-containing cells. Examples include nutrients (glucose, nicotinamide and retinoic acid), acids (butyrate), alkaloids (cyclopamine and conophylline) and pharmacological agents (LY294002 and wortmannin). These molecules, alone or in combination with specific growth factors and hormones, will likely provide key information to design specific culture media in order to obtain customized cells for implantation in diabetes. In addition, the study of such molecules will help to understand the mechanisms involved in stem cell biology as well as contribute to the design of specific drugs for islet repair and regeneration in diabetes.