The ETS family is a diverse group of transcription factors that control the expressions of genes that participate in an array of cellular activities, ranging from mitosis to apoptosis. As a consequence of regulating these processes, most ETS factors are oncogenic. However, there is growing evidence that ETS factors are also essential to regulation of the immune system. Of the 29 recognized ETS factors, nine are known to regulate genes involved in immunity, including Ets1, Ets2, GABP, Fli1, Elf1, MEF, ESE1, PU.1, and SpiB. These ETS factors typically activate the transcription of genes associated with pathogen and tumor defense, but several also demonstrate ability to repress transcription. Ets1 and PU.1 appear to have the greatest impact on immunity, primarily through their control of immune cell development. Alterations of Fli1 and Elf1 expression are associated with autoimmunity, emphasizing the role of ETS factors as not only positive, but also negative regulators of immunity. This review summarizes the roles of ETS factors in development of the immune system, defense against pathogens and malignancies, and self-tolerance.