Annexin A3 (ANXA3), also known as lipocortin III and placental anticoagulant protein III, has been reported to be dysregulated in tumor tissues and cancer cell lines, and harbors pronounced diagnostic and prognostic value for certain malignancies, such as breast, prostate, colorectal, lung and liver cancer. Aberrant expression of ANXA3 promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and therapy resistance to multiple chemotherapeutic drugs including platinum-based agents, fluoropyrimidines, cyclophosphamide, doxorubicin, and docetaxel. Genetic alterations on the ANXA3 gene have also been reported to be associated with the propensity to form certain inherited, familial tumors. These diverse functions of ANXA3 in tumors collectively indicate that ANXA3 may serve as an attractive target for novel anticancer therapies and a powerful diagnostic and prognostic biomarker for early tumor detection and population risk screening. In this review, we dissect the role of ANXA3 in cancer in detail.