Members of the interferon-regulatory factor family of transcription factors have long been known to be intracellular mediators of the effects of interferons. In recent years, interferon-regulatory factors have also been shown to have an essential role in the differentiation of T helper cells, both by modulating the functions of antigen-presenting cells and by having direct effects on the T helper cells themselves. Depending on the interferon-regulatory factor involved, the differentiation of T helper cells to either T helper 1 cells or T helper 2 cells can be influenced. In this article, we provide an overview of this relatively new and still underappreciated role of interferon-regulatory factors.