The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiologic studies have highlighted associations between increased serum leptin levels and increased tumor growth, whereas adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field. Clin Cancer Res; 19(8); 1926–32. ©2013 AACR.