Despite our best efforts to deceive the immune system, outwit pathogens, and improve upon the design of nature, there continues to be a need to improve the margin of safety of treatment for those with bleeding disorders. The current approach includes: (1) recombinant factor concentrates free of added proteins; (2) 'designer' factor molecules that enhance function and reduce immunogenicity; and (3) modulation of the immune system to suppress immune response in those who develop inhibitors. The hope is that through advances in our understanding of the coagulation and immune systems, treatment of haemophilia in the new millennium will be safer and less immunogenic. Currently available recombinant clotting factor concentrates include those produced: (1) with pasteurized human serum albumin in the cell culture medium as a stabilizer; (2) with bovine serum proteins in the cell culture medium; and (3) free of plasma derivatives. To the extent that current recombinant clotting factor concentrates contain even trace amounts of human or animal protein, there is continuing potential for transmission of nonenveloped viruses, including hepatitis A and parvovirus, and the theoretical potential for transmission of relatively unknown agents, such as prions (Creutzfeldt-Jakob disease or its variant). Second-generation recombinant factor concentrates that do not use human albumin as a stabilizer are currently in clinical trials, and third-generation recombinant factor concentrates currently in development take advantage of new strategies to achieve a 'protein-free' cell culture, purification, and final formulation. It is likely that improvement in safety and reduction in immunogenicity will require modification not only of antigenic structure but also of the immune response to coagulation proteins.