Midkine (MK) is a member of midkine family which is composed of MK and pleotrophin (PTN). MK behaves like a cytokine and growth factor, promotes the proliferation, differentiation, survival, adhesion, migration of cells. MK expression usually increases during ischemia, inflammation, tissue repair, neoplastic transformation and in different toxic conditions. Immune cells and most of organs have MK secretion function in fetal and adult life. MK could be a promising prognostic/diagnostic marker and a potential target in many of diseases including malignancy, toxic and inflammatory diseases. This review focuses on both cell protective and immune-modulatory roles of MK in different in vitro and in vivo disease models and human reports. MK is still a novel molecule in the regulation of organ development and the etiology of many diseases.