Insulin resistance is invariably present in patients with the cardiometabolic syndrome and is thought to play a key role in its pathogenesis. It represents a complex interaction of maladaptive characteristics related to impaired insulin action at target organs and external factors such as genetics and environment. It is likely that the molecular factors that underlie insulin resistance and resultant hyperinsulinemia contribute to many of the clinical components of the cardiometabolic syndrome, although the precise associations remain poorly understood. Abnormalities of various adipocytokines (particularly reduced circulating levels of adiponectin and leptin) resistance may also play a role in the genesis of insulin resistance. Genetic factors are an important determinant of insulin sensitivity. Effective management of the cardiometabolic syndrome will ultimately depend on our understanding of the underlying molecular mechanisms of key components of this disorder, such as insulin resistance.