Prophylaxis, the regular infusion of coagulation factor concentrates to severe hemophiliacs, has been an evolving therapeutic tool of management for the past three decades. Multiple clinical trials have and continue to be conducted in the field of prophylaxis in an attempt to determine ideal regimens of prophylaxis, its benefits, its risks and costs, and to address still unanswered questions; who to place on prophylaxis, when to start prophylaxis, when (if ever) to stop prophylaxis, etc. We present a detailed review and discussion of the evolution of prophylaxis as a tool in managing patients with hemophilia and we address the major issues and still unanswered questions.