Cytokines are important mediators of host defense and immunity, and were first identified for their role in immunity to infections. It was then found that some of them are pathogenic mediators in inflammatory diseases and much of the emphasis is now on pro-inflammatory cytokines, also in consideration of the fact that TNF inhibitors became effective drugs in chronic inflammatory diseases. The recent studies on the tissue-protective activities of erythropoietin (EPO) led to the term "tissue-protective cytokine." We discuss here how tissue-protective actions might be common to other cytokines, particularly those of the 4-alpha helical structural superfamily.