This article presents an overview of experimental studies that illustrate the vascular vs. myocardial selectivity of felodipine. The aim of our project was to develop a calcium antagonist that would selectively inhibit the activity of the myogenically active smooth muscle of the arterial resistance vessels without causing negative inotropic effects. In vitro, selectivity was tested as the concentration ratio at 50% inhibition of the peak force of paced papillary muscle and of the spontaneous myogenic activity of rat portal vein. The latter preparation has consistently been used as an in vitro model of myogenically active vascular (arterial) smooth muscle. It was found that dihydropyridines display different quantitative structure-activity relationships with regard to vascular and myocardial effects. Felodipine was the first compound synthetized that showed 100-fold vascular selectivity. In the same test system, Ca2+ chelators, La3+, and verapamil lacked selectivity. The high vascular selectivity of felodipine has been verified in vivo in various hemodynamic experiments. Thus, felodipine lowers arterial blood pressure due to reduced peripheral resistance without altering cardiac contractility. This is the case in various animal models and applies over a wide range of plasma concentrations whether autonomic nervous control is blocked or not. In contrast, nonselective compounds such as verapamil attenuate myocardial contractility in parallel with a reduction in peripheral resistance.