Recently, a novel type 1 diabetes association locus was identified at human chromosome 6p31.3, and TCF19 is a likely causal gene. Little is known about Tcf19, and we now show that it plays a role in both proliferation and apoptosis in insulinoma cells. Tcf19 is expressed in mouse and human islets, with increasing mRNA expression in non-diabetic obesity. The expression of Tcf19 is correlated with β-cell mass expansion, suggesting that it may be a transcriptional regulator of β-cell mass. Increasing proliferation and decreasing apoptotic cell death are two strategies to increase pancreatic β-cell mass and prevent or delay diabetes. siRNA-mediated knockdown of Tcf19 in the INS-1 insulinoma cell line, a β-cell model, results in a decrease in proliferation and an increase in apoptosis. There was a significant reduction in the expression of numerous cell cycle genes from late G1 phase through M phase and cells were arrested at the G1/S checkpoint. We also observed increased apoptosis and susceptibility to endoplasmic reticulum (ER)-stress after Tcf19 knockdown. There was a reduction in expression of genes important in maintenance of ER homeostasis (Bip, p58^IPK, Edem1, and Calreticulin) and an increase in pro-apoptotic genes (Bim, Bid, Nix, Gadd34, and Pdia2). Therefore, Tcf19 is necessary for both proliferation and survival and is a novel regulator of these pathways.