5'-AMP-activated protein kinase (AMPK) plays a pivotal role in maintaining energy and redox homeostasis under various metabolic stress conditions. Metabolic adaptation, which can be triggered by the activation of AMPK during metabolic stress, is the critical process for cell survival through the maintenance of ATP and NADPH levels. The importance of such regulation of fundamental process poses the AMPK signaling pathway in one of the most attractive therapeutic targets in many pathologies such as diabetes and cancer. In cancer, however, accumulating data suggest that the role of AMPK would not be simply defined as anti- or pro-tumorigenic, but it seems to have two faces like a double-edged sword. Importantly, recent studies showed that the anti-tumorigenic effects of many 'indirect' AMPK activators such as anti-diabetic biguanides are not dependent on AMPK; rather the activation of AMPK induces the resistance to their cytotoxic effects, emphasizing the pro-tumorigenic effect of AMPK. In this review, we summarize and discuss recent findings suggesting the two faces of AMPK in cancer, and discuss how we can exploit this unique feature of AMPK for novel therapeutic intervention.