There is a myriad of research in the pharmacological manipulation of skin flap survival. However, skepticism exists as to whether any of these drugs is clinically useful. We evaluated the efficacy of five categories of agents in improving skin flap survival in five different rat flap models. Diltiazem, isoxsuprine hydrochloride, nitroglycerin, prazosin hydrochloride (two doses), and methyldopa were compared in a double-blind, randomized fashion. Their benefits were assessed in a musculocutaneous flap, axial flap, and three types of random flaps. The “best” drug was determined to be nitroglycerin. Its efficacy was verified in a primate model.