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Hemophilias A and B are X-linked bleeding disorders that result in a qualitative or quantitative deficiency in coagulation factors VIII (FVIII) and IX (FIX), respectively. Affected patients experience significant morbidity as a result of repeated joint hemorrhages and subsequent arthropathy, and there is increased mortality related to life-threatening bleeding events. The mainstay of therapy is episodic or prophylactic infusions of plasma-derived or recombinant FVIII or FIX. However, gene transfer holds the promise of maintaining plasma levels of FVIII or FIX high enough to prevent the development of joint disease and reduce the risk of life-threatening bleeds or possibly even achieving normal plasma levels. Human gene therapy trials thus far have fallen short of this goal. This review summarizes the inherent limitations in expression of recombinant FVIII and the bioengineering strategies that are currently being explored for constructing novel recombinant FVIII molecules that have improved function. Current strategies for FVIII include increasing mRNA levels, improving secretion efficiency, increasing the rate of thrombin activation, stabilization of the activated form of FVIII, and strategies to prolong FVIII half-life in plasma by disrupting FVIII interaction with its clearance receptors. Strategies to improve the function of FIX include increasing the mRNA levels, reducing interaction with collagen IV, and increasing the specific activity. These novel molecules partnered with advances in gene transfer vector design and delivery may ultimately achieve persistent expression of FVIII and FIX, leading to an effective long-term treatment strategy for the hemophilias.