The transition of pancreatic progenitor cells to mature beta cells is regulated by the interaction of several transcription factors, including members of the sex-determining region on Y box (SOX) family of transcription factors. The SOX proteins are widely involved in cell fate determination and the development of several tissues, including bone, heart, gonads, lymphocytes, and glial cells as well as the pancreas. In this review, we will present recent findings that illustrate the critical role of SOX transcription factors in maintaining pancreatic progenitor cell pools and in controlling pancreatic islet morphogenesis and islet function. Interrelationships between the SOX family and other pancreatic transcription factors specific to endocrine lineages will also be discussed in light of islet cell-based therapies for the treatment of diabetes.