Over the past several years, platelet glycoprotein gene polymorphisms have received increasing attention as possible inherited determinants of prothrombotic tendency. However, their role in genetic susceptibility to thrombotic disease remains controversial. The glycoprotein IIIa Leu33Pro amino acid substitution appears to be associated with a subtle effect on platelet thrombogenicity in vitro, but is not a major risk factor for arterial thrombotic disease among the general population. Evidence suggests that the glycoprotein IIIa Pro33 allele may be associated with increased risk of thrombotic events following coronary re-vascularization and possibly among younger subjects with atherosclerosis. The nucleotide 807T variant of glycoprotein Ia is associated with increased platelet glycoprotein Ia/IIa receptor density, collagen-induced platelet adhesion and an increased risk of early onset myocardial infarction and stroke. Evaluation of the roles of the glycoprotein Ibalpha Thr145Met and variable number of tandem repeat polymorphisms has been complicated by their lack of well-defined effects on platelet adhesive function and the strong linkage disequilibrium between the two sites. Future epidemiologic studies of platelet glycoprotein gene polymorphisms will require larger sample sizes and family based approaches to further elucidate clinically important associations with thrombotic disease, including gene-environment and gene-gene interactions. Other polymorphisms of potential functional significance within genes encoding platelet membrane proteins will undoubtedly be discovered. The challenge will be to integrate advances in platelet biology with molecular and genetic epidemiology to enhance our understanding of the genetic determinants of common, but etiologically complex thrombotic diseases.