Upon their activation, CD4 T cells can differentiate into distinct T helper cell subsets with specialised functions. Different T helper cell subsets produce specific cytokines that mediate beneficial and sometimes detrimental effects, depending on the infection or disease setting. CD4 T cell priming relies on signals delivered by the T cell antigen receptor, co-stimulatory receptors and cytokine receptors on the CD4 T cell surface. Cytokine receptors are well known to deliver instructive signals that direct T helper cell differentiation. However, it is less appreciated that co-stimulatory receptors also exert potent modulatory effects on this process. In this review, we outline the contribution of co-stimulatory and co-inhibitory receptors to the process of T helper cell differentiation, focusing on those pathways for which the underlying mechanisms are best known. Herein, we depict the physiological context of T cell priming and emphasise the impact of cell-cell communication on directing T helper cell differentiation.Immunology and Cell Biology accepted article preview online, 24 March 2015. doi:10.1038/icb.2015.45.