In contrast to other diverse therapies for the X-linked bleeding disorder hemophilia that are currently in clinical development, gene therapy holds the promise of a lasting cure with a single drug administration. Near-to-complete correction of hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) have now been achieved in patients by hepatic in vivo gene transfer. Adeno-associated viral vectors with different viral capsids that have been engineered to express high-level, and in some cases hyperactive, coagulation factors were employed. Patient data support that sustained endogenous production of clotting factor as a result of gene therapy eliminates the need for infusion of coagulation factors (or alternative drugs that promote coagulation), and may therefore ultimately also reduce treatment costs. However, mild liver toxicities have been observed in some patients receiving high vector doses. In some but not all instances, the toxicities correlated with a T-cell response directed against the viral capsid, prompting use of immune suppression. In addition, not all patients can be treated because of preexisting immunity to viral capsids. Nonetheless, studies in animal models of hemophilia suggest that the approach can also be used for immune tolerance induction to prevent or eliminate inhibitory antibodies against coagulation factors. These can form in traditional protein replacement therapy and represent a major complication of treatment. The current review provides a summary and update on advances in clinical gene therapies for hemophilia and its continued development. © 2019 by The American Society of Hematology.