There is strong evidence for the association between obesity and cancer. Several retrospective and prospective observational studies have demonstrated that obesity and adiposity are independent risk factors for different types of cancer in both genders. According to a recent meta-analysis, a body mass index equal of higher than 40 kg/m2 determines a relative risk for the development of all cancers equal to 1.52 for males and 1.88 for females. The adipose tissues secretes several hormones, cytokines (named adipokines), inflammatory cytokines, factors related to complement and fibrinolysis, fatty acids, and enzymes. An increase in adiposity alters the homeostasis of those substances secreted by the adipose tissue and others (such as insulin and insulin-like growth factors). The pathophysiological bases of obesity-related cancer can be explained by alterations in adipokines levels, increase in insulin resistance, changes towards a proinflammatory state, and other effects such as increased oxidative stress. Leptin and adiponectin are the most abundant adipokines, and both play a major role in the pathogenesis of obesity-related cancer. In this chapter, the role of adipokines in the pathogenesis of obesity-related cancer, with emphasis on leptin and adiponectin, is discussed.