Atherothrombotic disease remains a major cause of mortality worldwide, and family clustering suggests an important contribution of genetic factors to disease pathogenesis. Thrombus formation represents the final step in atherothrombosis, a process influenced by genetic and environmental factors. A major difficulty of investigating the genetic regulation of thrombotic conditions is the complexity of the phenotype and the relatively modest effects of individual genetic variations. We address in this review genetic aspects involved in regulating thrombosis potential and their impact on the development of atherothrombotic disease. The effects of common genetic polymorphisms in clotting factors are discussed and examples of complex gene-gene and gene-environment interactions are highlighted. Understanding the effects of genetic factors on predisposition to thrombotic disease and unravelling the complex gene-environment interactions will help to better understand the pathophysiology of this complex condition, which will enable the development of new preventative and treatment strategies.