Prophylactic clotting-factor regimens reduce the occurrence of bleeding episodes and maintain joint health in individuals with moderate and severe hemophilia. However, these outcomes are only achieved with adherence to prescribed prophylaxis regimens. There are several types of barriers to adherence related to key patient, condition, treatment, health-care system, and/or socioeconomic variables. Notably, health-care professionals may not prescribe prophylaxis if they perceive that a patient will be nonadherent. Prophylactic treatment strategies should be developed with the patient and family, focused on individualized treatment goals. Personalized strategies are needed to reinforce the importance of and encourage confidence in administering the regular infusions required for prophylactic therapy. These strategies may include verbal and written information delivered by health-care professionals, peers, and inter-active media. The advent of extended half-life clotting factors requiring less frequent infusion may improve adherence.