The emergence of immune checkpoint inhibitors in the arsenal of cancer immunotherapy was a breakthrough which provided hope to many cancer patients. However, not long has passed since their discovery that some adverse effects were associated with these promising therapeutic agents. Immune checkpoint inhibitors dysregulate host immunity and may precipitate autoimmune diseases including diabetes mellitus. In this review, we go beyond the case reports towards understanding the underlying mechanisms by which Programmed cell death 1 (PD-1) and Programmed death ligand-1 (PD-L1) inhibitors precipitate diabetes. We discuss the role of PD-1/PD-L1 in autoimmunity and the use of mice models to describe their involvement in diabetes. We also reviewed the genetic anomalies in PD-1/PD-L1genes and their link to diabetes. Finally, we present the studies conducted to identify patients at risk of developing autoimmune diseases as an adverse effect for PD-1/PD-L1 use. Understanding these issues can guide researchers to find a way to circumvent the autoimmune adverse reactions seen with PD-1/PD-L1 inhibitors without affecting their antitumor activity.