Carcinogenesis involves a growing accumulation of genetic and epigenetic aberrations, leading to the deregulation of cellular homeostasis, followed by neoplastic progression. Although nutritional lipids play a critical role the specific transcriptional mechanisms involved in this process are not completely understood. In this review, we examine the biological effects of dietary essential fatty acids (n-3 and n-6 EFAs) and vitamin A, and the common pathways related to cancer chemoprevention. Eicosanoids (EFAs derivates) and retinoids (vitamin A derivates) are major mediators that act on their corresponding RXR-heterodimerized receptors (PPAR and RAR) and modify the carcinogenetic signalling pathways. Several effects of these mediators, mainly at DNA level, depend on specific molecular properties of the receptor isoforms and their differential affinities for their ligands, whose availability can be intentionally managed through diet. Nevertheless, the previous grade of differentiation in normal development or in cancer cells is an important modulatory factor of the cellular responses, especially when differentiating agents are evaluated. The potential of dietary EFAs and retinoids in chemoprevention and chemotherapy, through their actions on the cellular proliferation and differentiation processes, with particular reference to human breast cancer is discussed herein.