Major facilitator superfamily domain-containing protein-2a (Mfsd2a) which was considered as an orphan transporter has recently gained attention for its regulatory role in the maintenance of proper functioning of the blood-brain barrier. Besides the major role of Mfsd2a in maintaining the barrier function, increasing evidence has emerged with regard to the contributions of Mfsd2a to various biological processes such as transport, cell fusion, cell cycle, inflammation and regeneration, managing tumor growth, functioning of other organs with barrier functions or responses to injury. The purpose of this article is to review the different roles of Mfsd2a and its involvement in the physiological and pathophysiological processes primarily in the central nervous system and throughout the mammalian body under the lights of the current literature.