Celastrol, an active compound extracted from the Chinese medicine as used as a natural remedy for years. Although Celastrol has been shown to induce leukemia cell apoptosis, the involved molecular target has not been identified. Furthermore, whether Celastrol has antitumor activity in vivo has never been demonstrated. By the chemical structure and computational modeling analysis, Yang et al. hypothesized that Celastrol has proteasome-inhibitory and, therefore, antitumor activities. Indeed, Celastrol potently and preferentially inhibits the chymotrypsin-like activity of purified 20S proteasome (IC₅₀ = 2.5 µM) and 26S proteasome in human prostate cancer cells (1-5 µM) and tumors (1-3 mg/kg/day). Proteasome inhibition in vivo by Celastrol is accompanied by significant apoptosis and tumor growth inhibition (65-93%). Our results demonstrate that Celastrol is a natural proteasome inhibitor that has great potential for cancer prevention and treatment. The remaining challenge is to design, synthesize, and evaluate more potent and selective Celastrol analogs with no or little toxicity as proteasome inhibitors to suppress human tumor growth in clinical settings. The cover figure shows the chemical structure of Celastrol and its computational modeling image that demonstrates two carbons, C₂ and C₆ (indicated in red). These carbons possess high susceptibility toward a nucleophilic attack by the proteasome, suggesting that one or both could interact with and inhibit the proteasome. For details, see the article by Yang et al. on page 4758 of this issue.