Interferon regulatory factors (IRFs) consist of a family of transcription factors with diverse functions in the transcriptional regulation of cellular responses in health and diseases. IRFs commonly contain a DNA-binding domain in the N-terminus, with most members also containing a C-terminal IRF-associated domain that mediates protein-protein interactions. Ten IRFs and several virus-encoded IRF homologs have been identified in mammals so far. In response to endogenous and microbial stimuli during an immune response, IRFs are activated, and selectively and cooperatively modulate the expression of key cytokine and transcription factors involved in T helper cell differentiation in T cells and/or antigen-presenting cells. This review focuses on recent advances in the understanding of IRF-mediated transcriptional regulation in T helper cell differentiation and discusses the implications on the development of cellular and humoral immune responses and the pathogenesis of immune disorders.