The interferon-inducible p200 family proteins consist of a group of homologous human and mouse proteins that have an N-terminal Pyrin domain and 1 or 2 partially conserved 200 amino acid long C-terminal domains (designated the HIN domain or p200 X domain). These proteins display multifaceted activity due to their ability to bind to various target proteins (eg, transcription factors, signaling proteins, and tumor suppressor proteins) and modulate different cell functions. In addition to a role in interferon biology, increasing evidence supports a role for these proteins as regulators of various cell functions, including proliferation, differentiation, apoptosis, senescence, inflammasome assembly, and control of organ transplants. As a consequence, alterations in their expression and function may be of relevance in the pathogenesis of human diseases, such as systemic autoimmune syndromes, tumors, and degenerative diseases. This review summarizes the literature describing these data, highlights some of the important findings derived from recent studies, and speculates about future perspectives.