In addition to squamous cell carcinoma, the incidence of Barrett's esophagus with high-grade dysplasia and esophageal adenocarcinoma is rapidly increasing worldwide. Unfortunately, the current standard of care for esophageal pathology involves resection of the affected tissue, sometimes involving radical esophagectomy. Without exception, these procedures are associated with a high morbidity, compromised quality of life, and unacceptable mortality rates. Regenerative medicine approaches to functional tissue replacement include the use of biological and synthetic scaffolds to promote tissue remodeling and growth. In the case of esophageal repair, extracellular matrix (ECM) scaffolds have proven to be effective for the reconstruction of small patch defects, anastomosis reinforcement, and the prevention of stricture formation after endomucosal resection (EMR). More so, esophageal cancer patients treated with ECM scaffolds have shown complete restoration of a normal, functional, and disease-free epithelium after EMR. These studies provide evidence that a regenerative medicine approach may enable aggressive resection of neoplastic tissue without the need for radical esophagectomy and its associated complications.