Hormones, growth factors and cytokines produced by adipocytes are associated with cancer progression. We suggest that chronically elevated adipokines as observed in the obese state may have profound effects locally on colon epithelial cells through growth promotion effects, induction of autocrine signaling, angiogenesis and immune cross-talk. This dysregulation of the local environment via a systemic signal may lead to the promotion of colon cancer via a novel set of mechanisms. Elucidating the mechanisms by which obesity may increase cancer risk may lead to the identification of treatment/prevention targets. The use of models of this multistage process should allow for mechanism-based approaches to block phenotypes associated with the process of carcinogenesis. The review highlights using in vitro model systems of these various stages to understand the molecular mechanisms of obesity and cancer risk. The advantage in using these systems is that the response of cells possessing various transformations can be compared to “normal cells”. The key is to identify targets that are aberrant from normal to perturb for cancer prevention strategies. This approach would theoretically reduce the possibility of severe or unwanted side-effects when the target does not also destroy the normal cell mechanisms. Cell models can aid in the identification of those targets and inform rationale translation to animal and human studies.