2-Methoxyestradiol (2-ME) is a biologically active metabolite of 17beta-estradiol that appears to inhibit key processes associated with cell replication in vitro. The molecule has been suggested to have potent growth-inhibitory effects on proliferating cells, including smooth muscle cells and endothelial cells, and may be antiangiogenic. Because of these potential roles for 2-ME, its lack of cytotoxicity and low estrogenic activity, we hypothesize that 2-ME could be a valuable therapeutic molecule for prevention and treatment of cardiovascular diseases. Whether 2-ME is as effective in vivo as it is in vitro at modulating vascular processes remains controversial. Here we discuss recent developments regarding mechanisms by which 2-ME might regulate vascular activity and angiogenesis and speculate on the therapeutic implications of these developments.