Current attempts to improve the survival of cancer patients largely depend on strategies to target tumor cell resistance. Naturally occurring dietary compounds such as resveratrol have gained considerable attention as cancer chemopreventive agents. Here, we report that resveratrol acts as potent sensitizer for anticancer drug-induced apoptosis by inducing cell cycle arrest, which in turn resulted in survivin depletion. Concomitant analysis of cell cycle and apoptosis revealed that pretreatment with resveratrol resulted in cell cycle arrest in S phase and apoptosis induction preferentially out of S phase upon subsequent drug treatment. Likewise, cell cycle arrest in S phase by cell cycle inhibitors enhanced drug-induced apoptosis. Resveratrol-mediated cell cycle arrest sensitized for apoptosis by downregulating survivin expression through transcriptional and post-transcriptional mechanisms. Similarly, downregulation of survivin expression using survivin antisense oligonucleotides sensitized for drug-induced apoptosis. Importantly, downregulation of survivin and enhanced drug-induced apoptosis by resveratrol occurred in various human tumor cell lines irrespective of p53 status. Thus, this combined sensitizer (resveratrol)/inducer (cytotoxic drugs) concept may be a novel strategy to enhance the efficacy of anticancer therapy in a variety of human cancers.