Abstract Although the efficacy of antiplatelet therapy is supported by numerous studies areas of uncertainty and doubt persist both in secondary and in primary prevention. In both settings it can be surmised that, with few exceptions, the relative risk reduction obtained, for instance, with aspirin, is rather uniform across the different clinical conditions and measures “efficacy” of the drug: while the absolute risk reduction varies according to the risk levels of the different conditions, and expresses the “efficiency” of the treatment. Especially in conditions at high risk as the acute coronary syndrome (ACS) the problem of “variability of response” or “resistance” to antiaggregating drugs is of remarkable importance. For aspirin resistance main factors are low compliance, interferences with other drugs, especially NSAIDS, diabetes and related glication phenomenon, and especially fast platelet turnover. Genetic polymorphism (C50T) of COX1 gene, has been described but its significance is debated. Regarding clopidogrel, drug interferences, diabetes mellitus, increased platelet turnover, and polymorphisms of the cytochrome P450 family are involved. A useful expression of antiplatelet resistance is “High on Treatment Platelet Reactivity” (HTPR). This entity has been found predictive of poor outcome in a number of studies of patients with ACS, but not in all. Similarly, genotyping patients for cytochrome P450 polymorphisms also shows predictivity, but not confirmed in all studies. Both genotyping and measuring HTPR can be useful for selection of high risk ACS patients and especially in clinical research. New antiplatelet drugs as prasugrel, ticagrelor, and the recent vorapaxar seem to overcome the problem of resistance. In primary prevention, even assuming a uniform efficacy of aspirin, the risk and hence the absolute number of events spared are much lower. Therefore, aspirin will be less efficient, and the net clinical benefit over the bleeding risk will be smaller. Inconclusive results have been found in healthy people as well as in people with diabetes but no prior cardiovascular event. However, in a recent meta-analysis including new trials bearing some factors of heterogeneity, a small but significant reduction in overall mortality suggests that, for aspirin in primary prevention, “the game is not over”.