Each individual has an inherent variable risk of bleeding linked to genetic or acquired abnormal platelet number or platelet dysfunction. In contrast, it is less obvious that the variability of platelet phenotypes (number, mean platelet volume, function) may contribute to the variable individual risk of thrombosis. Interindividual variability of platelet indices or function may be either due to acquired factors, such as age, sex, metabolic variables, smoke, dietary habits, and ongoing inflammation, or due to genetic factors. Acquired variables explain a small portion of the heterogeneity of platelet parameters. Genetic factors, instead, appear to play a major role, although a consistent portion of such a genetic variance has not yet been attributed to any specific genetic factor, possibly due to the high number of DNA loci potentially involved and to the limited effect size of each individual SNP. A portion of variance remains thus unexplained, also due to variability of test performance. A major contradiction in present platelet knowledge is, indeed, the difficulty to reconcile the universally accepted importance of platelet indices or function and the lack of reliable platelet parameters in cardiovascular risk prediction models. Trials on antiplatelet drugs were generally designed to select a homogeneous sample, whose results could be applied to an average subject, tending to exclude the deviation/extreme values. As the current indications for antiplatelet treatment in primary or secondary prevention of ischemic vascular disease still derive from the results of such clinical trials where platelet function and its variability was not investigated, we cannot at present rely upon any current platelet test to either initiate, or monitor, or modify or stop treatment with any antiplatelet drug. Evidence is, however, increasing that traditional platelet aggregometry and other more recently developed platelet function assays could be useful to optimize antiplatelet therapy and to predict major adverse cardiac events.The observation of interindividual differences in platelet response to antiplatelet drugs has enlarged the spectrum and the possible clinical relevance of the variability of platelet indices or function. The development of personalized medicine will benefit from the concepts discussed in this chapter.