During the past year significant advances have been made in our understanding of the factors contributing to the differentiation of CD4+ T helper cell subsets. These have been driven, in part, by the realization that cytokines from the innate immune response, such as interleukin-12 (IL-12) and interferons (IFNs), play a critical role in T cell subset differentiation. This review covers some of the most recent data concerning the divergent role that IFNs have in the differentiation of human versus mouse T helper cell subsets. In this review we discuss the molecular basis for the specie-specific effect of type I IFN on the selective induction of Th1 type immune responses. Furthermore, since IFN-beta is used in the treatment of multiple sclerosis (MS) we discuss the potential effects of such treatment and the value of the Th1/Th2 paradigm in MS.