The various potential mechanisms contributing to nitrate tolerance are discussed. Pharmacokinetic alterations of the organic nitrate in the systemic circulation do not readily reflect pharmacologic tolerance. Neurohormonal changes do accompany continuous nitrate therapy, but the causative factor of tolerance, if it exists, has not been identified. Vascular metabolism of organic nitrates is impaired during in vitro nitrate tolerance, but it is still uncertain whether reduction in intracellular sulfhydryl availability is the operative mechanism. Vascular cyclic GMP production may be reduced during tolerance, but this change may not parallel that observed in vascular relaxation.