Infection with HIV-1 progressively erodes immune function, leading ultimately to multiple hematopoietic cytopenias. In advanced HIV disease, anemia, neutropenia, and thrombocytopenia occur in a large fraction of patients and are reflective of a striking inability of the bone marrow to accomplish a compensatory increase in production. No failure of compensatory production is greater than that of the T lymphoid system, where despite apparently effective control of HIV replication, restoration of anti-HIV immunity does not occur. Recent technical developments have provided considerable insight into hematopoietic dysfunction in HIV disease and, in particular, in vivo T cell generation. This article will review some of the mechanisms participating in immune regeneration, the stakes involved in effectively accomplishing full reconstitution, and potential approaches to enhance the limited endogenous regenerative process.