Hypoxia is one of the most common stresses that affect an organism's homeostasis. Although much is known of the mechanisms of the cellular and biochemical responses to acute hypoxia, relatively little is known of the mechanisms of the responses to prolonged or chronic hypoxia. Chronic hypoxia suppresses vascular smooth muscle contractility in many vascular beds. While the endothelium is likely to play a role, part of the mechanisms underlying chronic hypoxic-induced changes in vascular responses resides in the changes in receptor-mediated excitation-contraction coupling and/or signal transduction in the vascular smooth muscle. Recent studies have demonstrated that chronic hypoxia attenuates both receptor-second messenger and second messenger-contraction coupling efficiencies in the vascular smooth muscle. This suppression of pharmacomechanical coupling is likely to represent one of the adaptive mechanisms of vascular smooth muscle and to play an important role in an adjustment of vascular tone and blood flow under the stress of moderate chronic hypoxia.