Overexpressed cell-surface receptors play a crucial role as biomarkers in immunodiagnostics and immunotherapy. Epithelial cell adhesion molecule (EpCAM) is a 40 kDa cell-membrane glycoprotein associated with cell differentiation, survival, migration, and proliferation. The structure, biological functions, and role of EpCAM in tumorigenesis have been extensively studied, including its involvement in metastasis, tumor cellular signaling, and pro-proliferating pathways. It is differentially overexpressed on the surface of several tumor types, with substantial evidence suggesting a positive correlation with poor disease prognosis and overall survival. Consequently, it has emerged as a significant target for immunotherapy development, with some of them already entering clinical evaluation and one having been approved by the U.S. Food and Drug Administration to date. Pre-clinical and clinical studies evaluating anti-EpCAM immunotherapies have reported diverse outcomes necessitating critical assessment in considering future therapy development. EpCAM-targeting immunotherapies including monoclonal antibodies, adoptive cell transfer therapy, immunocytokines, recombinant immunotoxin, and bispecific T-cell engagers have been studied as monotherapy or in combination with other treatments resulting in improved outcomes. Depending on disease status, EpCAM-targeting therapies are studied in adjuvant and neoadjuvant settings by integrating the clinical features of patients and treatment intent. However, the wide range of adverse events reported in various unsuccessful clinical studies has implications for future clinical trial designs, patient stratification, and endpoint criteria measures. This review examines the efficacy and toxicity profiles of anti-EpCAM immunotherapeutic approaches that have undergone clinical investigations for the treatment of antigen-positive malignancies and provides perspectives to guide future research and development strategies toward precision medicine.