During chronic infections and cancer, T cells progressively lose function and become exhausted. However, effective T-cell responses are necessary to ultimately control viral infections and tumors. Hence, strategies that either restore endogenous immune responses or provide functional T cells by adoptive immunotherapy need to be explored. CD8 T cells play a prominent role in viral infections, as well as cancer, but CD4 T cells are necessary to support CD8 T-cell function. In addition, CD4 T cells exert direct effector functions, induce optimal B-cell responses and orchestrate innate immunity. Therefore, we propose that adoptive transfer strategies should exploit CD4 T cells alone or in combination with CD8 T cells, for the treatment of chronic infections and cancer. Furthermore, since adoptively transferred cells are subject to exhaustion, combining adoptive transfer therapy with immunotherapies that inhibit T-cell exhaustion should maximize the longevity and success rate of responses.