There is much interest in the factors that control the cytokine profile of T-helper (Th) lymphocytes, and attention has focused on feedback from the cytokines themselves. In general, Th1 cytokines promote Th1 activity and inhibit Th2 activity, and vice versa. Both Th1 and Th2 responses should therefore be stable. However, in vivo, many responses start predominantly as Th1 and then shift to Th2. Why do they do this? As discussed here, an important influence on this shift that has been largely ignored in in vitro work is the endocrine system.