Unraveling the exact signaling events mediating the distinct functions of the T cell–derived cytokines interleukin-4 (IL-4) and IL-13 has been challenging because they are structurally similar and share a functional signaling receptor chain. A study now proposes a potential molecular mechanism to explain the functional differences between IL-4 and IL-13 that involves the ability of IL-4, but not IL-13, to effectively activate the insulin receptor substrate–2 (IRS-2) signaling cascade through binding to its receptor. A better understanding of the interactions of IL-4 and IL-13 with their cognate receptors may facilitate the development of therapies without unintended side effects.