Abstract We show that the synthetic oleanane triterpenoid, CDDO-methyl ester (CDDO-Me; methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate) is an effective agent for suppressing angiogenesis, both in cell culture and in vivo. The potency of CDDO-Me is particularly striking when dosed in vivo to inhibit the angiogenic effects of vascular endothelial growth factor and tumor necrosis factor-α in Matrigel sponge assays; activity is seen at i.p. doses of CDDO-Me as low as 0.003 mg/kg of body weight. If the Matrigel sponges are impregnated with CDDO-Me just before implantation in the mice, picomolar doses of CDDO-Me will suppress angiogenesis. CDDO-Me also inhibits growth of endothelial cells in monolayer cultures and suppresses neovascular morphogenesis in three-dimensional cultures, but significantly higher doses (50-200 nmol/L) are required. We also show antiangiogenic effects of CDDO-Me on xenografts of Kaposi's sarcoma cells in immunocompromised mice, using CD31 as a marker. Several known individual molecular targets of CDDO-Me and related triterpenoids that are relevant to all of these findings include nuclear factor-κB signaling, signal transducers and activators of transcription signaling, and transforming growth factor-β signaling, as well as Keap1, the endogenous inhibitor of the transcription factor Nrf2. However, the particularly potent antiangiogenic activity seen in vivo in the present experiments suggest that CDDO-Me, as an angioprevention agent, may be interacting with an entire network of molecular and cellular targets, rather than at a single molecular locus or in a single-cell type. [Mol Cancer Ther 2007;6(12):3139–46]