Several gene products play pivotal roles in the induction of inflammation and the progression of cancer. The Raf kinase inhibitory protein (RKIP) is a cytosolic protein that exerts pleiotropic activities in such conditions, and thus regulates oncogenesis and immune-mediated diseases through its deregulation. Herein, we review the general properties of RKIP, including its: (i) molecular structure; (ii) involvement in various cell signaling pathways (i.e., inhibition of the Raf/MEK/ERK pathway; the NF-kB pathway; GRK-2 or the STAT-3 pathway; as well as regulation of the GSK3Beta signaling; and the spindle checkpoints); (iii) regulation of RKIP expression; (iv) expression’s effects on oncogenesis; (v) role in the regulation of the immune system to diseases (i.e., RKIP regulation of T cell functions; the secretion of cytokines and immune mediators, apoptosis, immune check point inhibitors and RKIP involvement in inflammatory diseases); and (vi) bioinformatic analysis between normal and malignant tissues, as well as across various immune-related cells. Overall, the regulation of RKIP in different cancers and inflammatory diseases suggest that it can be used as a potential therapeutic target in the treatment of these diseases.