Type 2 diabetes mellitus (T2DM) is a complex disorder that has a heterogeneous genetic and environmental background. In this Review, we discuss the role of relatively infrequent polymorphisms of genes that regulate insulin signaling (including the K121Q polymorphism of ENPP1, the G972R polymorphism of IRS1 and the Q84R polymorphism of TRIB3) in T2DM and other conditions related to insulin resistance. The biological relevance of these three polymorphisms has been very thoroughly characterized both in vitro and in vivo and the available data indicate that they all affect insulin signaling and action as well as insulin secretion. They also affect insulin-mediated regulation of endothelial cell function. In addition, several reports indicate that the effects of all three polymorphisms on the risk of T2DM and cardiovascular diseases related to insulin resistance depend on the clinical features of the individual, including their body weight and age at disease onset. Thus, these polymorphisms might be used to demonstrate how difficult it is to ascertain the contribution of relatively infrequent genetic variants with heterogeneous effects on disease susceptibility. Unraveling the role of such variants might be facilitated by improving disease definition and focusing on specific subsets of patients.