Forearm plethysmography coupled with brachial artery drug administration and the Aellig technique in hand veins coupled with local venous drug administration are both extremely powerful tools, now widely available to the clinical pharmacologist. These techniques allow precise assessment of drug effects on vascular smooth muscle in vivo, without the confounding influences of drug effects on other organs or activation of neurohumoral reflexes. These local techniques allow the direct study of human vascular physiology, pharmacology, and pathophysiology in vivo in humans. In addition, they can form an important part of the early clinical development programme for new cardiovascular drugs, including drugs affecting the renin-angiotensin system and the sympathetic nervous system, as well as the novel agents arising from research on the vascular endothelium. Given the power of these techniques, it is important to consider where studies in patient volunteers might answer particular questions better than experiments in animal models of disease.