1. The effects of compounds with α 2 -agonist and α 2 -antagonist properties on human forearm blood flow and on isolated human arterial segments have been studied. 2. The findings from these studies in vivo and in vitro did not provide evidence in support of the hypothesis that postsynaptic α 2 -receptors mediate smooth muscle contraction in the tissues under investigation. 3. The constriction of the forearm vascular bed in response to low intra-arterial doses of idazoxan (RX 781094), an α 2 -antagonist, provides evidence for a physiological role for a presynaptic α 2 autoregulatory mechanism. 4. The variability of the forearm vascular responses to higher doses of idazoxan highlights the pitfalls that may have misled previous authors in their interpretation of the results of similar studies. A U-shaped dose-response curve to compounds with mixed α 2 -and α 1 -antagonist properties may be constructed, which emphasizes the importance of the dose-dependent selectivity of these antagonists at α 2 - and α 1 -receptors. 5. The effect of idazoxan on the responses of arterial segments in vitro to exogenous catecholamines was dependent on the integrity of the endothelium, and provides evidence that α 2 -receptors may mediate release of the endothelium-derived relaxing factor.