Major progress has occurred in the field of hemophilia in the last decade, much more so in the past 5 years. The most obvious of these are the whole range of newer therapeutic products, both conventional and longer acting clotting factor concentrates, as well as other novel products for hemostasis in patients with hemophilia, which will not only improve the quality of care but also address the issue of access to care.1,2 Apart from this, another area that has very significantly advanced is that of outcome assessment of hemophilia care.3,4 After nearly two decades of no progress since the early 1980s with regard to clinimetric instruments to measure relevant outcomes, the last decade saw renewed interest in the field and a plethora of outcome assessment tools being generated. Add to these, the recent recognition of phenotypic heterogeneity of this disease even within the same severity groups not only in terms of their bleeding profiles,5 but also the extent of joint damage as a result of bleeding,6 and the varied pharmacokinetic responses to clotting factor concentrates.7 All these advances are having major impact on how we define this disease as well as set paradigms for its management. It, therefore, seemed like a good opportunity to bring together some of those leading these efforts in the world to contribute to this issue of Seminars in Thrombosis & Hemostasis, which is devoted to capturing these advances and their impact on clinical practice and research in this field. The Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis recently published, through its subcommittee of FVIII and IX, definitions for several relevant clinical and laboratory events and outcomes in hemophilia.8 The first article in this issue by Blanchette and Srivastava9 addresses the background to that publication. It is indeed quite amazing that in a diseasewhere somany events and practices are only clinically characterized, the only definitions that were provided by any international scientific organization till very recently were for its clinical severity and inhibitors levels.10 This had led to a situation where several independent groups had developed their own definitions for the studies they wished to conduct, leading to lack of harmonization of data collection and reporting. Hopefully, these issues will be addressed to a great extent through these updated definitions. Of course, the remaining challenges will need to be addressed in the future as more data are available. While it has been long recognized that even severe hemophilia is clinically heterogeneous, it is onlymore recently that the biological basis for these differences is being understood better. While the initial literature described the differences in clinical bleeding,11 the differences in the response to bleeding, particularly in the joints, have only recently been described among patients with severe hemophilia.12 Both the hemostasis aspects and the joint changes can be studied better now. For the former, the tools that assess global hemostasis have been able to show clear differences that correlate with the clinical phenotype.13 This is an advance that is attempting to move the field forward from the simplistic definition based on factor levels < 1% only. Nogami and Shima, therefore, make a detailed description of the data that support this heterogeneity from these assessments.14 Though joint bleeding has long been recognized as the hallmark of this disease, its pathogenesis has been poorly understood. Recent studies in human tissues examined ex vivo as well as studies on models of chronic hemarthroses in animal models have clearly shown the importance of inflammatory cytokine polymorphisms apart from the hemostatic variables.15,16 Blobel et al,17 therefore, review this literature and describe how the leads from thisfield, aswell as that from others related to joint disease such as rheumatoid arthritis, can be pursued in suitable transgenic animal models to study the basis and extent of phenotypic heterogeneity of this disease. It should be appreciated that ultimately the goal of such work is not just better understanding of the biology of hemophilia, but also the ability to predict the clinical course and decide the intensity of the replacement therapy that should be offered. While regular replacement therapy with clotting factor concentrates (CFC) has completely transformed the lives of