The hypothesis that a high-fat diet promotes the development of postmenopausal breast cancer is supported by international data showing a strong correlation between fat intake and breast cancer rates and a modest positive association with high-fat diet in case-control studies. Dietary fat intake was found to be unrelated to the risk of breast cancer in cohort studies. In view of these conflicting findings it has been difficult to make nutritional recommendations for the prevention of breast cancer. Studies in animal models and recent observations in humans, however, have provided evidence that a high intake of omega-polyunsaturated fatty acids (PUFAs), stimulates several stages in the development of mammary and colon cancer, from an increase in oxidative DNA damage to effects on cell proliferation, free estrogen levels to hormonal catabolism. In contrast, fish oil-derived omega-3 fatty acids seem to prevent cancer by influencing the activity of enzymes and proteins related to intracellular signalling and, ultimately, cell proliferation. In this commentary, current evidence from experimental and human studies is summarized that implicates a high intake of omega-6 PUFAs in cancer of the breast, colon and, possibly, prostate and which indicates that omega-3 PUFAs and monounsaturated fatty acids such as oleic acid (omega-9) are protective. Plausible mechanisms for modulation of steps in the multistage carcinogenesis process by fats are discussed. Properly designed epidemiological studies are now needed, that integrate relevant biomarkers to unravel the contributions of different types of fat, their interactions with hormonal catabolism, protective nutritional factors and human cancer risk.