Colorectal cancer (CRC) is a multifactorial disease with several hypothesized etiologic factors including inflammatory processes; hormones such as estrogen, androgen, and insulin; and energy-related factors. We present evidence that integrates these elements in a pathway we call the convergence of hormones, inflammation, and energy-related factors (CHIEF). First, given the physiology of the gut, substantial epidemiologic and molecular data support the hypothesis that activation of innate immunity in the normal gut mucosa by various environmental agents (commensal bacteria, dietary antigens, mucosal irritants, pathogens) and endogenous factors such as estrogen, androgens, and insulin levels provokes basal inflammation as an underlying factor of the association of insulin, estrogen, and energy-related factors with CRC. Second, critical genes involved in this pathway, e.g., phosphatase tensin homologue on chromosome 10 (PTEN) and serine threonine kinase 11 (STK11)/LKB1, are tumor suppressor genes often mutated in intestinal cancer or CRC. Third, laboratory experiments show that cellular PTEN and STK11/LKB1 tumor suppressor enzymes are vulnerable to inactivation by redox-active species, especially chemically reactive lipid mediators of inflammation and redox stress. Epidemiologic data further support the underlying proposal that CHIEF comprises important elements of CRC risk. Although this discussion of the CHIEF pathway focuses on CRC, we believe that this pathway may play an important role in the etiology of other cancers as well.