Since CD4+ T cell help has been proposed to be required for maintaining the activity of tumor-specific CD8+ T cells, tolerance in tumor-specific CD4+ T cells may seriously impair the efficacy of therapeutic tumor vaccines. To overcome this problem, we devised a strategy to “engineer” CD4+ T cell help by treating tumor-bearing animals with nonmyeloablative conditioning and transplantation of autologous hematopoietic stem cells (HSCs) that have been genetically modified, via lentiviral transduction, to express an antigen containing “foreign” CD4+ T cell epitopes. After hematopoietic reconstitution, animals received the combination of an autologous tumor cell vaccine and an infusion of primed CD4+ T cells specific for the expressed epitopes. Using influenza hemagglutinin (HA) as the model antigen, we first confirmed that transplantation of HA-transduced HSCs led to efficient expression of HA by antigen-presenting cells, as demonstrated by the clonal expansion of adoptively transferred, HA-specific CD4+ transgenic T cells in mice receiving HA-transduced HSCs but not in mice receiving nerve growth factor receptor (NGFR) gene-transduced HSCs. Next, BALB/c mice harboring 13 day old, metastatic 4T1 mammary cancer were treated with removal of the primary, nonmyeloablative conditioning and transplantation of HA-transduced syngeneic HSCs, and following hematopoietic reconstitution, with concomitant autologous tumor cell vaccination and adoptive transfer of in vitro activated, HA-specific transgenic CD4+ T cells. This therapy was successful in curing the majority of tumor bearing mice, and was superior to the same therapy given to mice transplanted with NGFR-transduced stem cells. Finally, we found that the anti-tumor effect of vaccination plus exogenous T cell help was abolished by the adoptive transfer of either CD4+ or CD8+ T cells from tumor-bearing mice, suggesting that tumor-bearing mice contain both potential effectors and suppressors of anti-tumor immunity, the latter of which are abolished by the non-myeloablative conditioning. These results highlight the importance of CD4+ T cell help in the induction of therapeutic anti-tumor immunity.