NKX2.2 is a homeodomain transcription factor involved inneuroendocrine and glial differentiation. It is notablyupregulated in Ewing’s sarcoma through activation by theEWS-FLI1 oncogenic fusion protein. Because Ewing’ssarcoma is one of many “small round blue cell tumors,” itsdiagnosis can be challenging based on morphology alone.NKX2.2 has emerged as a sensitive marker fordistinguishing Ewing’s sarcoma from other morphologicallysimilar tumors when used as part of an antibody panel.In research, NKX2.2 provides valuable insight into tumorbiology, differentiation pathways, and gene regulation insarcomas and glial tumors.