Insulin resistance (IR) and impaired glucose-stimulated insulin secretion (GSIS) are the two primary pathophysiological abnormalities leading to the development of type 2 diabetes (T2D). Over the past two decades, a large body of work has implicated enhanced delivery of fatty acids to non-adipose tissues in the development of both IR and impaired GSIS. As the net whole-body import of fatty acids occurs in the postprandial state, tissue fatty acid overexposure has been linked to this physiological state. Although many advances have been made in our understanding of these lipotoxic effects at the cellular level, the precise mechanisms of lipotoxicity at the whole-body level in humans during the development of T2D is still a subject of debate. Important advances continue to be made in our understanding of the mechanisms that regulate postprandial fatty acid delivery to tissues and their metabolism. This review focuses on those mechanisms and on the potential implication of their dysregulation for tissue lipotoxicity in the development of T2D.