Over the past 40 years, the prevalence of obesity has increased epidemically worldwide, which raises significant concerns regarding public health and the associated economic burden. Obesity is a major risk factor for several conditions including cardiovascular disease and type 2 diabetes, and recent evidence suggests that obesity negatively affects cancer risk and outcome. The relationship between obesity and cancer is complex and involves multiple factors both at the systemic and cellular level. Indeed, disruptions in insulin metabolism, adipokines, inflammation, and sex hormones all contribute to the adverse effects of obesity in cancer development and progression. The focus of this review will be the impact of these systemic obesity-related factors on cancer biology, incidence, and outcome. Potential therapeutic interventions and current clinical trials targeting obesity and its associated factors will also be discussed.