The World Health Organization (WHO) has recently reinforced the fact that inadequate diets, along with physical inactivity, are among the ten main determinant factors of mortality. Several randomized trials demonstrated that dietary interventions may lower or even prevent the occurrence of several non-communicable diseases. In this context, the role of diet has been exhaustively evaluated in several clinical and epidemiological studies. Thus, it is well established in literature that the amount and type of dietary fat have a direct influence on cardiovascular risk factors, such as lipids and plasma lipoprotein concentration, as well as their association with inflammatory processes. Fatty acids also participate in complex intracellular signaling systems, a function which has been currently investigated. Dietary polyunsaturated fatty acids (PUFA) act not only by altering membrane lipid composition, cellular metabolism and signal transduction, but also modulating gene expression by regulating the activity and/or production of different nuclear transcription factors. The aim of this article is to review important topics regarding the lipids metabolism and correlate them with nutritional therapies that may contribute to the prevention and treatment of related diseases.