PROBLEM STATEMENT: The development of a potent vaccine that can help treat tumors resistant to conventional cytotoxic therapies remains elusive. While part of the problem may be that trials have focused on patients with bulky residual disease, the desire to maximize responses to the vaccine remains. APPROACH: The gamma(c) family of cytokines offer a unique opportunity to support the expansion and effector potential of vaccine-responding T-cells, as well as stimulate other effectors, such as natural killer (NK) cells, to become activated. RESULTS: Combining vaccines with cytokines seems logical but can bring unwanted toxicity, as has been observed with interleukin (IL)-2. In addition, the nonspecific activation or expansion of unwanted cell subsets, such as regulatory T-cells, can contribute to global immunosuppression and limit vaccine responses. The development of IL-7 and IL-21 for the clinic offers the promise of enhancing anti-tumor responses but with far less systemic toxicity and no expansion of regulatory T cells. Preclinical studies demonstrate that IL-15 could also improve T-cell, and especially NK-cell, responses as well. CONCLUSIONS/RECOMMENDATIONS: Future work should expand the use of vaccines with IL-7, IL-21 and hopefully IL-15 in high-risk patients, and consider treatment while in a state of minimal residual disease to maximize benefit. Identifying tumors that can signal through gamma(c) cytokines will also be essential so that induction of relapse will be avoided.