Although familial clustering of venous thromboembolic events was observed at the start of this century, it was not until the late nineteenseventies before our insight into the organization of the haemostatic and fibrinolytic systems was sufficiently complete to enable a start to be made on a systematic search for genetic defects associated with familial thrombosis. The discovery that heterozygosity of antithrombin deficiency co-segregated with the thrombotic tendency in affected families seemed to make a strong case for the association between single gene defects and thrombosis. The results of these systematic studies had been in part very fruitful and could be considered in the context of two principle endogenous anticoagulant pathways (Fig. 1), the antithrombin-heparan sulphate pathway and the protein C/protein S (PC/PS) pathway. However, only three single gene disorders had been identified that were associated with a significant increase in the risk for venous thrombembolism in families identified through a symptomatic deficient patient, with one of antithrombin, PC or PS deficiency. The awareness that in 85% of families predisposed to thrombosis no explanation could be found for the clustering of this disorder, stimulated the search for alternative approaches. A major breakthrough in the study of familial thrombosis has been achieved during the past two years. Firstly, the concept and investigation of activated protein C resistance (APC-R) was introduced and, secondly, a mutation in the factor V gene (1691 G-> A in exon 10, leading to 506Arg to Gin) was identified as the molecular basis for the phenotype of APC-R in the large majority of affected individuals (2, 3). This mutation, which is associated with a significant increase in thrombotic risk (3-5), has been found in about 50% of selected families with thrombophilia and in 20% of consecutive patients with thrombosis. A consequence of this advance has been a conceptual change in how thrombophilia is viewed, which has implications for diagnosis and treatment of the disorder. This review [published in two parts, see also (6)] attempts to summarise recent progress and to present recommendations for diagnosis, treat ment and research in developed and developing countries.