CD146 was initially identified as a marker of melanoma in 1987. The research history of more than 30 years revealed its physiological functions in early development, immune response, metabolism, and pathological functions in inflammation, autoimmune diseases, tumor and pregnancy diseases. The understanding of the functional mechanisms of CD146 has also changed from mediating cell migration as an adhesion molecule to receiving extracellular signals and activating various intracellular signaling pathways as a cell membrane receptor. The correlation of CD146 to various diseases, especially its roles in tumors, inspired the application explorations of CD146 in diagnosis, prognosis and targeted therapy of those diseases, some of which has entered the clinical stage. In this review, to understand CD146 in an all-round way and develop its application potential in biomedicine, we comprehensively reviewed and summarized the research history of CD146 and addressed the prospect of the fundamental questions in its research and development.