Current dogma suggests that the positive correlation between obesity and cancer is driven by white adipose tissue that accompanies obesity, possibly through excess secretion of adipokines. However, recent studies in fatless A-Zip/F-1 mice, which have undetectable adipokine levels but display accelerated tumor formation, suggest that adipokines are not required for the enhanced tumor development. The A-Zip/F-1 mice are also diabetic and display elevated circulating levels of other molecules frequently associated with obesity and carcinogenesis: insulin, insulin-like growth factor-1, and inflammatory cytokines. Therefore, we postulate that the pathways associated with insulin resistance and inflammation, rather than adipocyte-derived factors, may represent key prevention or therapeutic targets for disrupting the obesity-cancer link.