Phospholipid transfer protein (PLTP) plays an essential role in lipoprotein metabolism. Deficiency or overexpression of PLTP in animal models results in modulation of the atherosclerotic process. Moreover, PLTP has also been implicated in obesity and diabetes, underscoring its versatile nature and its central role in the pathophysiology of these tightly connected disease states. The purpose of this article is to assess the current evidence on the role of PLTP in all these conditions. This evidence strongly suggests that PLTP may become a therapeutic target.