T cells are well adapted to sense and respond to cues from their environment. Cytokine cues are particularly important when T cells are first activated. During their initial activation, the cytokine milieu directs the differentiation of T cells towards a particular T helper program while suppressing other fates. Production of T helper-specific cytokines by naive T cell must be prevented to force their dependence on outside cues. If these cues are not provided, or are inappropriately interpreted, the immune response will fail to develop appropriately. This could result in excessive stimulation, and lead to allergy or autoimmunity. In contrast, inadequate responses could lead to immunodeficiency. In this review, we illustrate this dichotomy using TGF-β and IL-4, two cytokines that, when delivered in the presence of IL-2, can drive cells towards the inducible regulatory T (iT_reg) cell or the T_H2 cell program. Interestingly, TGF-β and IL-4 antagonize one another and actively suppress the differentiation program induced by the other. Furthermore, the combination of the two signals drives T cells to adopt a different helper program that is characterized by production of the cytokine IL-9, thus defining them as T_H9 cells. Recent data has revealed key mechanisms by which IL-4 and TGF- β promote and/or suppress T_H2 and iT_reg cell differentiation programs. Additionally, the molecular pathways that result from the cooperation of TGF-β and IL-4, resulting in T_H9 generation, have been recently defined. We will integrate these new findings and discuss how defects in pathways that help T cells interpret these external cues lead to inappropriate immune responses and can have deleterious consequences.