It is well known that omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) control some key molecular cell mechanisms, resulting in a beneficial role in inflammatory diseases. Such mechanisms are complex and reflect the diversity of their functions, mainly as modulators of the dynamic properties of membranes, regulators of gene expression and as precursors of active mediators. In the present review we aim to summarize the state of the art of the effects and mechanisms by which omega-3 LC-PUFAs such as eicosapentaenoic acid (EPA, C22:5 omega-3) and docosahexaenoic acid (DHA, C22:6 omega-3) regulate different metabolic processes to maintain homeostasis. Thus, we will describe some aspects of these fatty acids—from their structural function in cell membranes to their role as regulators of gene expression, mainly in lipid metabolism. However, further studies are required in order to elucidate these actions and to have a better understanding in regard to the beneficial effects of omega-3 LC-PUFAs in the pathogenesis of several diseases as well as their functions as nutrients with protective action to avoid or delay development of these diseases. Furthermore, it is necessary to highlight the lack of comprehensive studies including nutritional, biochemical, genetic and immune aspects in order to identify specific molecular mechanisms involved in the beneficial effects of consumption of DHA (C22:6 omega-3) and EPA (C22:5 omega-3) and their metabolic derivatives on health promotion.