Hemophilia is a congenital disorder that commonly results in musculoskeletal bleeding and orthopedic complications. After an acute joint hemorrhage, there is pain, swelling, and limited motion due to an increase in intra-articular pressure and inflammation. Increases in intra-articular pressure induce mechanical signals that lead to cartilage cell apoptosis. Repeated bleeding results in development of a target joint, which is characterized by painless swelling and limited motion. Blood in the joint space provokes a proliferative disorder termed hemophilic synovitis (HS), with characteristics resembling those of malignant tumors. It has been suspected that one or more of the many components of blood, particularly iron, may be responsible for initiating and sustaining the inflammatory and synovial/vascular cell proliferation response associated with recurrent joint hemorrhages. In this paper, we review the pathogenesis of HS and present experimental data from mice deficient in factor VIII or IX activity in order to clarify the pathways by which blood in the joint space results in arthropathy. Understanding these pathways and cataloguing their key components may identify new targets for therapy of HS.