Abstract The increasing prevalence of obesity brings forward its importance as a risk factor for cancer development, particularly in the gastrointestinal tract. Obesity may trigger cancer development through several mechanisms, where metabolic deregulation of adipokines can modulate multiple oncogenic molecular pathways. Leptin and adiponectin are the most well-studied adipokines, and their imbalance can trigger different tumorigenic responses. Both epidemiologic and experimental studies have associated leptin with increased cancer risk and cell responsiveness in carcinogenesis and tumor invasion. On the other hand, adiponectin is reported to elicit the opposite effect. In addition to circulating or tissue adipokine levels, adiponectin, and leptin receptors or genetic polymorphisms may also play a role in cancer development. Moreover, adiponectin and leptin modulation offer valuable therapeutic approaches. We will review the links underpinning obesity and cancer development and focus on discussing the pathophysiological roles of leptin and adiponectin.