Systemically distributed proteins such as clotting factors have been traditionally expressed from muscle or liver to achieve therapeutic, long-term expression. As long-lived cell capable of generating an abundant progeny, hematopoietic stem cells (HSCs) also merit consideration for this purpose. To be clinically relevant, this approach would require that hematopoietic cells be capable of expressing high levels of functional, secreted proteins, that the risk of insertional oncogenesis be minimized, and that sufficient stem cell engraftment be achieved following minimally invasive conditioning. Recent reports demonstrate the feasibility of expressing either factor IX (FIX) or factor VIII (FVIII) in erythroblasts and platelets using lineage-restricted vectors, resulting in effective treatments in mouse models of hemophilia. The erythroid system is especially powerful in providing high protein output, yielding FIX levels approaching 1 micro g/ml per vector copy in the plasma of long-term hematopoietic chimeras, a secretion level that vastly outperforms any other current mammalian constitutive or long-terminal repeat (LTR)-driven vector system. These early but promising studies raise the prospect of further developing these strategies for clinical investigation.