Myocyte Enhancer Factor 2D (Mef2D) is a member of the Mef2 family. As a transcription factor, Mef2D regulates the expression of genes that impinge on cellular viability, tissue development, and fuel metabolism. Interestingly, Mef2D function appears to be tissue dependent. The function of Mef2D appears to be tissue-specific, with differences in activity in the immune system, neuronal tissue, and muscle. Here, we review the published literature describing the role of Mef2D across tissues. Little is known about the role of Mef2D in the beta-cell. To determine the function of Mef2D in the beta-cell, we built overexpression and knockdown cell lines. We determined the effect of Mef2D overexpression or knockdown on mitochondrial respiration, insulin secretion, cell survival, and gene expression in the INS-1 832/13 beta-cell line. Our data demonstrates that Mef2D knockdown enhances mitochondrial respiration, insulin secretion, and cell survival. Conversely, Mef2D overexpression inhibits mitochondrial respiration, insulin secretion, and cell survival. We demonstrate that some of this effect is due to modulated expression of the mitochondrial gene mtND6. These findings demonstrate that Mef2D overexpression is detrimental to beta-cell function and that Mef2D knockdown is beneficial. These data suggest that Mef2D may be a viable target to enhance functional beta-cell mass as a treatment for Type 1 and Type 2 Diabetes.