The ability of CD4+ T helper (Th) cells to differentiate into two phenotypes distinguished by their cytokine profile is a major determinant of the type of immune response elicited by bacterial, viral or parasitic infections. The development of Th1 cells is associated with delayed-type hypersensitivity and cell-mediated immune responses while Th2 responses are associated with humoral immunity and allergic inflammation. While these phenotypes exist at the extremes of the immune response and are associated with pathological conditions, there is an enormous plasticity that allows reversibility and the development of a wide array of cytokine profiles. There has been considerable interest in determining the signals and transcription factors that govern the differential production of the Th1 and Th2 cytokines. There are now several candidate transcription factors that may play a role in skewing the cytokine profile in a distinct direction. Because of the plasticity of the system, these transcription factors must be able to respond to environmental signals in a very subtle manner and not simply be on/off switches for expression of the cytokine genes. The architectural transcription factor high mobility group (HMG) I(Y) is a modulator of the function of many of the transcription factors that control cytokine gene transcription. HMGI(Y) appears to play either a positive or negative role depending on the cytokine promoter and its ratio to other transcription factors. It is proposed that HMGI(Y) may have a role in regulating the production of cytokines in favour of a given immune response.