The unprecedented emergence of novel therapeutics for both hemophilia A and B during the last half decade has been accompanied by the promise of even more extraordinary progress in ameliorative and curative strategies for both disorders. Paradoxically, the speed of innovation has created new dilemmas for persons with hemophilia and their physicians with respect to optimizing individual choices from the expanding menu of standard and novel therapies and approaches to symptom or risk reduction, and ultimately, to normalizing the hemophilia phenotype. Among the most disruptive new approaches, challenges remain in the form of the adverse reactions that have been observed with nonfactor therapies, as well as in the uncertain long-term safety profile of potentially curative gene therapy. Together, these challenges have generated uncertainty as to how to adopt novel therapies and treatment strategies across a diverse patient population, creating speed bumps on the hemophilia innovation highway. It is from this perspective that this article discusses the current state of gene therapy and bleeding prophylaxis for hemophilia A and B, as well as prevention and treatment of the factor VIII inhibitor phenotype in hemophilia A. It further posits that these speed bumps may provide important clues to the mechanistic understanding of both symptom manifestation and resilience within the hemophilia phenotype, as well as opportunities to reconsider and reconfigure the current paradigms for symptom prediction and individualized therapeutic decision making.