The concept to use the human skin microcirculation as a pharmacological in-vivo test system is old; however, methods developed in the 50s have been abandoned because of side effects and/or use of radioactive substances. We describe a newly developed minimally invasive method that allows in-vivo pharmacology in the human skin microcirculation injecting very low doses of a substance of drug without any systemic effects. The double injection technique (DIT) bears the potential to predict the effects of a drug and/or the vascular reactivity or dysfunction of other less accessible areas of the circulation (e.g. the myocardium). The DIT has been applied for studies in healthy volunteers and patients with atherosclerosis; the focus of interest was endothelial (dys-)function and the effect of exogenous vasoactive drugs. Using endothelin antagonists, we investigated the role of endogenous endothelin under physiological conditions and in atherosclerosis. The NO-synthase inhibitor L-NMMA has been applied to study the L-arginine-NO-pathway and the role of endothelial adrenoceptors. Ongoing studies with the DIT comparing coronary and skin microcirculation may help to develop minimally invasive methods to predict the effects of drugs and vascular function in the heart.