Background: Raf kinase inhibitory protein (RKIP) belongs to the phosphatidylethanolamine binding protein (PEBP) family that is expressed in both prokaryotic and euakaryotic organisms. Objective: In this review, we discuss the role of RKIP as a modulator of signal transduction, the relationship of RKIP to other members of the PEBP family, and the role of RKIP in human health and disease. Results/conclusion: In mammals, RKIP regulates activation of MAPK, NF-κB and G protein coupled receptors (GPCRs). As a modulator of key signaling pathways, RKIP affects various cellular processes including cell differentiation, the cell cycle, apoptosis and cell migration. Emerging evidence suggests that RKIP is implicated in several human diseases or disorders, among them metastatic tumorigenesis and Alzheimer's disease.