Recombinant DNA technology and protein engineering are creating hope that we can address ongoing challenges in hemophilia care such as reducing the costs of therapy, increasing the availability to the developing world, and improving the functional properties of these proteins. Technological advances to improve the half-life of recombinant clotting factors have brought long-acting clotting factors for hemophilia replacement therapy closer to reality. Preclinical and clinical trial results are reviewed as well as the potential benefits and risks of these novel therapies. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.