Omega-3 (or n-3) polyunsaturated fatty acids (PUFAs) and their metabolites are natural ligands for peroxisome proliferator receptor activator (PPAR)gamma and, due to the effects of PPARgamma on cell proliferation, survival, and differentiation, are potential anticancer agents. Dietary intake of omega-3 PUFAs has been associated with a reduced risk of certain cancers in human populations and in animal models. In vitro studies have shown that omega-3 PUFAs inhibit cell proliferation and induce apoptosis in cancer cells through various pathways but one of which involves PPARgamma activation. The differential activation of PPARgamma and PPARgamma-regulated genes by specific dietary fatty acids may be central to their distinct roles in cancer. This review summarizes studies relating PUFAs to PPARgamma and cancer and offers a new paradigm relating an n-3 PUFA through PPARgamma to the expression of the cell surface proteoglycan, syndecan-1, and to the death of cancer cells.