The purpose of this article is to provide an overview that summarizes much in the way of our current state of knowledge regarding the pathogenesis and natural history of type 1 diabetes in humans. This information is presented to the reader as a series of seminal historical discoveries that, when advanced through research, transformed our understanding of the roles for the immune system, genes, and environment in the formation of this disease. In addition, where longitudinal investigations of these three facets occurred, their roles within the development of type 1 diabetes, from birth to symptomatic onset and beyond, are discussed, including their most controversial elements. Having an understanding of this disorder’s pathogenesis and natural history is key for attempts seeking to understand the issues of what causes type 1 diabetes, as well as to develop a means to prevent and cure the disorder.