Members of the common gamma chain (cytokine family include IL-2, IL-15, IL-4, IL-7, IL-9, and IL-21) hold important roles in driving the immune cell landscape of many disease pathologies. Upon ligand binding, the common gamma chain is recruited to the ligand-bound cognate receptors to direct lymphocytes’ responses. Current engineering themes to potentiate the therapeutic applications of these cytokines include de novo designs (IL-2/IL-15), half-life extensions such as albumin fusion (IL-2, IL-4, IL-15), Fc fusion (IL-2, IL7, IL-12, IL-15), and PEGylation (IL-2, IL-12, IL-15), tumor antigen or lymphocyte targeting using antibody fusions (IL-2, IL-12, IL-21).