CD99 is a transmembrane protein involved in many cellular functions, including cell adhesion and migration, endocytosis and exocytosis, and intracellular protein trafficking. It is highly expressed in all leukocyte lineages, Sertoli cells, granulosa cells, and pancreatic islet cells. Due to alternative splicing, there are two isoforms of CD99 that differ at the carboxy terminus. CD99 Type I (CD99wt) is the full-length form containing 185 amino acids and CD99 Type II (CD99sh) contains 161 amino acids. Their expression is differentially regulated and they may have opposite functions in different contexts. CD99 is expressed in many types of tumors and has been used for differential diagnosis of conventional Ewing sarcoma. It has been actively pursued as a therapeutic target. On the other hand, CD99 may also play a tumor suppressor role in other tumors, such as Hodgkin’s lymphomas, osteosarcomas, and pancreatic tumors.