Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome resulting in BCRABL fusion protein. Though there are a few treatment options drug resistance is often encountered. The drug resistance in CML is attributed to the elevated levels of HSP70 chaperone protein. Resveratrol (Res) is a phytoalexin produced by several plants. We studied the chemotherapeutic effects and mode of action of Res on K562 (CML) cells. Res was found to be non-cytotoxic to the normal lymphocytes but induced apoptosis in K562 cells in a time dependent manner. This was established by cell cycle analysis by flow cytometry, caspase-3 activity measurement, trypan blue cell viability assay, nuclear fragmentation and microscopy. The pro-survival protein PKB/Akt and the transcription factor HSF1 were identified as the molecular targets of Res. The activation of these proteins by phosphorylation was impeded by Res, as confirmed by western blot analysis. The decrease of transcriptional activity of HSF1 was determined by EMSA and promoter assay by HSF1-SEAP vector. Res treatment also caused suppression of Hsp 70 both at the mRNA and protein level, which was not caused by caspases. The downregulation of Hsp70 expression in the presence of Res was dependent on Akt as shown by using Akt siRNA and by inhibition of the upstream Akt activator PI3K using LY294002. Moreover, Res exerted additive effects on the chemotherapeutic efficacy of 17-allylamino-17- demethoxygeldanamycin (17AAG), an anti-cancer agent by significantly enhancing apoptosis induction. We conclude that resveratrol possibly acts at one or more steps downstream of Bcr-Abl by and blocking Akt and HSF1 phosphorylation and and for the first time report its unique property to downregulate hsp70 gene expression in K562 cells.