Based on epidemiological studies and meta-analyses, the World Cancer Research Fund (WCRF) panel stated that red meat is a convincing cause of colorectal cancer. Recently, the IARC/WHO classified red meat consumption as “probably carcinogenic to humans” (Group 2A). Red meat contains high concentrations of heme iron that induces lipid peroxidation in the colon lumen and the subsequent formation of secondary lipid oxidation products such as 4-hydroxynonenal (HNE). HNE was found in foodstuffs in relatively high concentration, particularly in meat and processed meat. Moreover, HNE formation possibly occurs in the digestive tract when rats receive heme iron and a PUFA-rich oil at the same time. In vivo studies in rats show that the development of preneoplastic lesions is well correlated with heme-iron and HNE content of the diet, and also with the urinary excretion of the major metabolite of HNE, the mercapturic acid of 1,4-dihydroxynonene (DHN-MA). Secondary oxidation products of PUFA, and especially HNE, could be one of the missing links between heme iron, enhanced luminal lipid peroxidation and colon cancer development. In vitro studies in mouse epithelial colon immortalized cells show that the cells mutated on the Apc (Adenomatous polyposis coli) gene, an early and frequent mutation during the development of human colorectal cancer, were more resistant to HNE than non-mutated cells. This resistance is due to a better metabolization capacity of those cells towards HNE. The enzymes involved are under the transcriptional control of Nrf2/antioxidant responsive element (ARE) pathway, a pathway that is upregulated in Apc mutated cells. Nrf2 natural inducers, as curcumin, have a protective effect both in vitro and in vivo.