It has been well known that resveratrol inhibits the proliferation of various cancer cells. AMP-activated protein kinase (AMPK), a sensor of cellular energy status, has emerged as a potent target for cancer prevention and/or treatment. It has been found that the activation of AMPK by resveratrol was crucial for the inhibition of HT-29 colon cancer cells. Resveratrol strongly inhibited phosphorylation of Akt. The possibility whether AMPK activation was essential to the inhibition of p-Akt was investigated in resveratrol-treated cancer cells. The inhibitory effect of resveratrol on Akt was not observed when AMPK activities were blocked by the treatment with AMPK siRNA at a relatively lower level of resveratrol. However, the higher concentrations of resveratrol inhibited Akt without the activation of AMPK. Therefore, it was concluded that resveratrol could modulate Akt AMPK-dependently or AMPK-independently. The inhibition of Akt along with the activation of AMPK may contribute to the unraveling anti-cancer mechanism of resveratrol.