The transcription factor Nkx6.1, when overexpressed in primary rodent and human islets, is sufficient to enhance beta cell proliferation, increase insulin secretion and enhance cell survival. We have sought to define the transcriptional targets of Nkx6.1 that allow for its ability to increase functional beta cell mass. We have shown that Nkx6.1 induces expression of the transcription factor CEBP𝛼. CEBP𝛼 overexpression is sufficient to induce proliferation of Ins-1 832/13 beta cells and primary rat islets. CEBP𝛼 overexpression enhances glucose stimulated insulin secretion from primary rat islets, while decreasing total insulin content. Finally, CEBP𝛼 overexpression protects Ins-1 832/13 beta cells from thapsigargin and glucolipotoxicity induced cell death but fails to protect against etoposide and camptothecin induced cell death. These data suggest that CEBP𝛼 plays a critical role in Nkx6.1 mediated expansion of functional beta cell mass through protecting against endoplasmic reticulum induced stress. We demonstrate the effect of CEBP𝛼 on gene transcription of genes essential for modulating endoplasmic reticulum induced stress.