IFN-gamma has long been recognized as a signature proinflammatory cytokine that plays a central role in inflammation and autoimmune disease. There is now emerging evidence indicating that IFN-gamma possesses unexpected properties as a master regulator of immune responses and inflammation. In this issue of the JCI, Guillonneau et al. show that indefinite allograft survival induced by CD40Ig treatment is mediated by CD8(+)CD45RC(low) T cells through the production of IFN-gamma (see the related article beginning on page 1096), supporting the emerging view that IFN-gamma is critical in the self-regulation of inflammation. These contradictory roles of IFN-gamma, perhaps best understood by the principle of yin and yang, represent one of nature's paradoxes, whereby the same cytokine functions as an inducer as well as a regulator for inflammation. Understanding this complex process of IFN-gamma signaling is essential, as it has therapeutic implications.