Current treatment of hemophilia A by intravenous infusion of factor VIII (fVIII) concentrates is very costly and has a potential adverse effect of developing inhibitors. Gene therapy, on the other hand, can potentially overcome these limitations associated with fVIII replacement therapy. Although hemophilia B gene therapy has achieved promising outcomes in human clinical trials, hemophilia A gene therapy lags far behind. Compared to factor IX, fVIII is a large protein which is difficult to express at sustaining therapeutic levels when delivered by either viral or non-viral vectors. To improve fVIII gene delivery, numerous strategies have been exploited to engineer the fVIII molecule and overcome the hurdles preventing long term and high level expression. Here we reviewed these strategies, and discussed their pros and cons in human gene therapy of hemophilia A.