Signal transducer and activator of transcription 4 (STAT4) is a central mediator in generating inflammation during protective immune responses and immune-mediated diseases. In the 8 yr since their first description, STAT4-deficient mice have defined the role of STAT4 in a variety of in vivo model systems. Despite the extensive study and use of these mice, the exact role of STAT4 in vivo is still unclear. In this review, I focus on describing the phenotypes of STAT4-deficient immune responses to pathogens and in diseases. Comparing the effects of STAT4 deficiency among numerous model systems will further enhance the development of a systemic model of STAT4 function in vivo.