Interleukin 6 (IL-6) and IL-27 signal mainly through both of the signal transducers STAT3 and STAT1 but induce distinct effects. In Immunity, Hirahara et al. evaluate the specificity and redundancy of the transcriptomic changes induced by these two cytokines in CD4+ T cells. The duration, intensity and dimer composition of the STAT1 and STAT3 response is specific to each cytokine, which activate roughly equal amounts of shared and unique sets of genes. Analysis of the gene-expression profiles and genome-wide compensatory binding of STAT1 and STAT3 in CD4+ T cells deficient in either STAT3 or STAT1 shows that STAT3 controls the bulk of the transcriptional output of both cytokines either as a homodimer or a STAT1-STAT3 heterodimer, whereas STAT1 provides the specificity of the responses to each cytokine, with STAT1 homodimers regulating genes uniquely induced by IL-27 and genes specifically repressed by IL-6. Thus, combinatorial use of signaling or transcriptional units allows unique responses to signals that share these units.