RAF kinase inhibitor protein (RKIP) is an essential regulator of intracellular signaling. A somatic loss of RKIP expression is a frequent event in solid human cancers, and a role of RKIP as metastasis-suppressor is widely accepted nowadays. Recently, RKIP loss has been described in acute myeloid leukemia (AML) and a series of other myeloid neoplasias (MNs). Functional in vitro and in vivo experiments revealed that RKIP is an essential player within the development of these liquid tumors; however, the respective role of RKIP seems to be complex and multi-faceted. In this review, we will summarize the current knowledge about RKIP in myeloid leukemogenesis. We will initially describe its involvement in physiologic hematopoiesis, and will then proceed to discuss its role in the development of AML and other MNs. Finally, we will discuss potential therapeutic implications arising thereof.