The recognition that CD4+ T-cell responses could be divided into at least two functional subsets either dominated by production of interferon (IFN)-gamma and associated with cell-mediated immunity (Th1) or characterized by production of interleukin (IL)-4 and IL-5 and associated with humoral immunity (Th2) provided a basis to understand the role of T cells in resistance or susceptibility to different types of pathogens. As a consequence, many studies have focused on the identification of cytokines that influence these events. For example, the development of Th1-type responses is largely dependent on IL-12. However, other cytokines also affect this process, and initial studies revealed that IL-27, a cytokine with close structural and functional similarity to IL-12, can promote Th1 responses required for immunity to Leishmania major. Subsequent work with IL-27R (WSX-1)-deficient mice infected with Toxoplasma gondii or Trypanosoma cruzi revealed that the IL-27/IL-27R system can act as a negative regulator of inflammatory T-cell responses. The aim of this review is to discuss recent studies from these laboratories on the role of IL-27 in immunity to parasitic infections in the context of previous work and to highlight the pleiotropic effects of the IL-27/IL-27R system in the development and regulation of Th1 and Th2 responses.