There is considerable evidence that insulin and insulin-like growth factors regulate a number of important physiological functions in a variety of tissues, some not considered to be classically insulin sensitive. Impaired biological responses to insulin and related insulin-like growth factors are referred to as insulin resistance. Persons with insulin resistance often display clinical abnormalities other than impaired glucose tolerance, including central obesity, hypertension, dyslipidemia, microalbuminuria, and abnormal coagulation and fibrinolytic systems. The mechanisms leading to development of insulin resistance are not fully understood. However, in addition to abnormalities of phosphorylation processes, it appears that alterations in cellular cation metabolism contribute to diminished cellular actions of insulin (i.e., glucose transport and hemodynamic actions). This review focuses on known cellular cation abnormalities and associated insulin resistance and cardiovascular disease.