Cancer is the second leading cause of death in the United States, and mortality due to colorectal cancer is only surpassed by lung cancer. Epidemiological studies demonstrate that dietary polyunsaturated fats can have a profound effect on colorectal cancer risk. Experimental data indicate that modulation of cellular (n-6) PUFA metabolism can affect the progression of the disease. This paper discusses the role (n-6) PUFA play in promoting intestinal tumorigenesis and how dietary PUFA from different families interact to modify the neoplastic process. Dietary PUFA that attenuate arachidonic acid metabolism [such as (n-3) PUFA] have antineoplastic properties, whereas those that augment arachidonic acid metabolism, such as linoleic, gamma-linolenic, and arachidonic acids do not appear to enhance tumorigenesis when added to the Western diet but may diminish the beneficial effects of other dietary lipids. It is the relative contributions of the different dietary PUFA that may determine overall risk for and progression of the disease.