Dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) have potent biological effects on the blood(cells), the vasculature and the myocardium. In the epidemiological studies in which the benefit from the regular ingestion of n-3 PUFAs was reported, the responsible mechanisms remain obscure. A great deal of the PUFA-effect can be explained by the known interference with the eicosanoid metabolism. Many processes, believed to be involved in atherogenesis such as adhesion and infiltration of bloodcells (in)to the vasculature, platelet aggregation, secretion of endothelium-derived factors and mitogenic responses of vascular smooth muscle cells are partially mediated by receptor-activated phospholipases C-β and A2. As PUFAs take part at many steps of the signalling pathways, the latter could represent important action sites to beneficially interfere with atherogenesis. In this brief review, we have discussed the results of studies on the influence of alteration of PUFA composition of the membrane phospholipids or of exogenously administered non-esterified PUFAs on phospholipid signalling. For convenience, we have mainly focused our discussion on those studies available on the myocardium. By changing the PUFA composition of the phospholipids, the endogenous substrates for the membrane-associated phospholipase C-β and A2 are changed. This is accompanied by changes in their hydrolytic action on these substrates resulting in altered products (the molecular species of 1,2-diacylglycerols and the non-esterified PUFAs) which on their turn evoke changes in events downstream of the signalling cascades: activation of distinct protein kinase C isoenzymes, formation of distinct eicosanoids and non-esterified PUFA effects on Ca2+ channels. It has also become more clear that the membrane physicochemical properties, in terms of fluidity and cholesterol content of the bilayer, might undergo changes due to altered PUFA incorporation into the membrane phospholipids. The latter effects could have consequences for the receptor functioning, receptor-GTP-binding protein coupling, GTP-binding protein-phospholipase C-β or A2 coupling as well. It should be noted that most of these studies have been carried out with cardiomyocytes isolated from hearts of animals on PUFA diet or incubation of cultured cardiomyocytes with non-esterified PUFAs in the presence of albumin. Studies need to be performed to prove that the PUFA-diet induced modulations of the phospholipid signalling reactions do occur in vivo and that these effects are involved in the mechanism of beneficial effects of dietary PUFAs on the process of atherosclerosis.