PBX3 is a homeodomain-containing transcription factor of the pre-B cell leukemia (PBX) family, members of which have extensive roles in early development and some adult processes. It plays crucial roles in embryonic development, organogenesis, and cell differentiation by regulating the expression of downstream target genes. Beyond its physiological functions, PBX3 is increasingly recognized for its significant involvement in oncogenesis. It is frequently overexpressed in various malignancies, including leukemias and solid tumors, where it promotes cell proliferation, inhibits apoptosis, enhances invasion and metastasis, and contributes to chemotherapy resistance.