The control of coagulation factor levels has a pivotal role in thrombophilia and known functional polymorphisms explain only a minor part of the coagulation factor level variance. Several studies provide evidence for i) interaction of polymorphisms and their combination with environmental factors; ii) molecular mechanisms mediating activation of coagulation proteins by environmental factors; iii) molecular mechanisms mediating transcriptional control of thrombophilia genes by environmental factors. However, the vast majority of molecular regulation by environmental factors is still unknown. Understanding of gene-gene and gene-environment interactions will require a detailed knowledge of regulatory regions of thrombophilia genes and of regulatory proteins.