Green tea and its major active component, epigallocatechin-3-gallate (EGCG), have been reported to have anticancer activity on various cancers. However, the exact molecular mechanism of its anticancer activity is still not well understood. We investigated the anticancer activity of green tea extract (GTE) and EGCG on 3 human squamous carcinoma cell lines (CAL-27, SCC-25, and KB) in vitro. We also examined the effects of GTE and EGCG on cell signaling networks using our newly developed Pathway Array technology, which is an innovative proteomic assay to globally screen changes in protein expression and phosphorylation. Our results demonstrated that GTE and EGCG inhibited all 3 squamous carcinoma cells' growth via S and G(2)/M phase arrest, but different sensitivities to GTE and EGCG in different cell lines were observed: CAL-27 cells were more sensitive to the both agents than SCC-25 and KB cells, and GTE at an EGCG equivalent concentration displayed a stronger inhibition than EGCG alone. The Pathway Array assessment of 107 proteins indicated that different signaling pathways were activated in different cell lines, suggesting heterogeneity at the signaling network level. After treatment with GTE or EGCG, a total of 21 proteins and phosphorylations altered significantly in all 3 cell lines based on analysis of variance (ANOVA) (P < 0.05). The major signaling pathways affected by GTE and EGCG were EGFR and Notch pathways, which, in turn, affected cell cycle-related networks. These results suggested that GTE and EGCG target multiple pathways or global networks in cancer cells, which resulted in collective inhibition of cancer cell growth. The finding pointed out the future direction to study the underlying mechanism of the chemotherapeutic and chemopreventive activities of EGCG and GTE.