Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its beta-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described. The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease.