Endothelial cells (ECs) assume arterial- or venous-specific molecular characteristics at early stages of development. These lineage-specific molecular programmes subsequently instruct the development of the distinct vascular architectures of arteries and veins. Now, on p. 1173, Jau-Nian Chen and co-workers investigate the role that these early molecular programmes play in angiogenesis. Using the zebrafish caudal vein plexus as a model for venous-specific angiogenesis, they identify a new compound, aplexone, as an inhibitor of venous, but not arterial, angiogenesis. They show that aplexone targets the HMG-CoA reductase (HMGCR) pathway and that injection of mevalonate, a metabolic product of HMGCR, into zebrafish embryos reverses the effect of aplexone on venous angiogenesis. They also show that the inhibitory effect of aplexone on venous angiogenesis in zebrafish and human ECs is mediated by HMGCR-regulated membrane targeting of the small GTPase RhoA through protein prenylation. These and other findings indicate that angiogenesis is differentially regulated by the HMGCR pathway in an arteriovenous-specific manner in both zebrafish and human ECs.