The incidence of obesity in the western world has increased dramatically during recent decades. Epidemiological data suggest that obesity is associated with an increased risk of several but not all types of cancers, with clear sex-specific differences. The underlying mechanisms are still a matter of debate. This review focuses on the potential factors linking obesity to cancer. Current experimental evidence suggests that insulin resistance and a chronic, subclinical inflammation in the visceral fat are the major metabolic events causing alterations in the levels of insulin, glucose, free fatty acids, insulin-like growth factor 1 (IGF-1) and 2, adipose tissue-derived proinflammatory cytokines and other bioactive molecules, such as adipokines (e.g. leptin and adiponectin), vascular endothelial growth factor (VEGF), sex hormones, gut microbiota and secondary bile acids. All these factors may act directly or indirectly on the tumor microenvironment to drive tumor progression via stimulation of cell survival/antiapoptosis, cell proliferation, angiogenesis and invasion/metastasis of the cancer cells. Therapeutic strategies that target dysfunctional or inflamed fat and have been shown to benefit patients include bariatric surgery, while other cell or hormone-directed interventions, such as conversion of visceral fat macrophages to an anti-inflammatory M2 phenotype or the pharmacological modulation of serum adipokine levels are still theoretical and need to be clinically evaluated for their ability to successfully treat or prevent obesity-related cancers.