Next to water, tea is the most popular beverage in the world. The most abundant and active compound in green tea is (-)-epigallocatechin-3-gallate (EGCG), which is extensively studied for its cancer-preventive and anti-cancer activities as well as its cellular targets. One potential molecular target of EGCG is the proteasome. While molecular docking and structure-activity relationship (SAR) analysis suggests that the ester carbon of EGCG is important for mediating its proteasome-inhibitory activity, EGCG is very unstable under physiological conditions. Therefore, a series of analogs were synthesized aiming to improve stability and bioavailability of EGCG. Among them, peracetate-protected or the prodrug of EGCG was found to have increased bioavailability, stability, and proteasome-inhibitory activities against various human cancer cells and tumors compared to EGCG, suggesting its potential use for cancer prevention and treatment. Epidemiological studies have indicated that green tea consumption is associated with the reduced risk of cancers, especially associated with the reduced risk of late stage of cancers. This risk reduction may be attributed not only to proteasome inhibition, but also to numerous other intracellular molecules targeted by EGCG that are involved in cell cycle regulation, apoptosis, angiogenesis, and metastasis.