The incidence of diabetes in humans is increasing in many countries around the world. In order to minimize the risk of diabetes in our population, it is important to identify and understand the mechanisms that trigger the disease. The Introduction to the article provides a brief overview of the common types of diabetes and how β-cell demise contributes to this. This is followed by an introduction to the normal and abnormal morphology of the endocrine pancreas, the processes of insulin synthesis and secretion, along with commonly used research tools to study diabetes. The bulk of this article will largely focus on the toxicology of the pancreatic β-cells and the mechanism(s) contributing to β-cell demise. While the cause of diabetes has historically been largely attributed to a sedentary culture and poor diet, there appears to be a set of “nontraditional” contributions from medication use, smoking, and environmental contaminants which we have also extensively described.