Differential radiographic criteria are unreliable for the histological diagnosis of periradicular lesions of pulpal origin. It should not, therefore, be assumed that large lesions or lesions with an opaque border are cystic. Even if cystic, or if strands of epithelium are present, the literature supports repair following the removal of the source of the pathosis. In most cases, the aetiological factors are oral contamination through the root canal or degenerating pulpal tissue. Therefore, the mere surgical removal of lesions of pulpal origin without removing the causes through proper root canal cleaning, shaping and obturation, will not result in the healing of the periradicular tissues. In addition to removing effectively the causative factors, environmental changes in the periradicular tissues caused by the process of canal debridement may inherently aid in the demise of epithelium, when present. The salient issues are discussed in light of thorough debridement of the root canal system, coupled with postulated mechanisms for the resolution of lesions displaying epithelial stands or cavities. Likewise, the role of calcium hydroxide and its potential role in the alteration of the periradicular environment is addressed, with support for the repair of large periradicular lesions without surgical intervention.