Cytokines that signal through receptor complexes containing the common gamma (gammaC) chain receptor subunit are central regulators of lymphocyte homeostasis. In this review, we discuss the four major gammaC cytokines that have proven activity in or potential for immunotherapy: IL-2, IL-7, IL-15 and IL-21. Their shared and unique activities on specific lymphocyte populations suggest therapeutic applications such as enhancing lymphocyte reconstitution, expanding tumor and pathogen-specific lymphocytes, and optimizing vaccines. Because the responsiveness of individual lymphocyte subsets varies under different situations such as lymphopenia and active immune responses, understanding the dynamics of gammaC-containing receptor expression is important in deciding how to achieve the most desired effect. Current understanding of the biology of gammaC cytokines suggests several clinical applications, including their direct administration or use in generation of lymphocytes for adoptive transfer, increasing their endogenous production, and potentiating their activity by complex formation with specific antibodies or their specific receptor-alpha subunits. Overall, gammaC cytokines have great potential, through their targeted use alone or in combination, to be an integral part of clinical interventions with enhanced efficacy and decreased toxicity.