A heparin-binding growth factor and cytokine midkine (MK) is a highly expressed retinoic acid–responsive gene protein during embryogenesis. Under physiological conditions, MK is continued to be expressed at low levels throughout adulthood, determined mainly in the renal tubular cells, endothelium, epidermis, bronchial epithelium, and lymphocytes. The serum levels of the healthy accepted population are generally below 1000 pg/mL. MK takes a significant part in both the homeostasis of healthy tissue and the development of disease. The MK levels are abundantly high in many human malignancies including cancer, and MK seems to modulate the occurrence, recurrence, and progression of cancer through increasing cell growth, cell survival, cell metastasis, cell migration, and angiogenesis. Several studies have reported the role of MK as a specific biomarker for the detection, prognosis, treatment modality determination, and monitorization of several cancer types. I hereby summarize the current knowledge with innovative approaches and future perspectives about the participation of MK in cancer occurrence and progression.