Human epithelial cells encounter two senescence barriers that enforce a limited proliferative potential. A first barrier is mediated by the retinoblastoma protein, and can be overcome by multiple types of errors, many of which are observed in human cancers. A second, extremely stringent telomere-dependent barrier, is a consequence of repression of telomerase activity. Although relieved by ectopic hTERT expression, the nature of the errors required to overcome this latter barrier during in vivo carcinogenesis have not yet been defined. Attainment of immortality and telomerase reactivation are crucial to human carcinoma development; the derangements responsible for attainment of immortality may be rate-limiting and permissive for further progression to malignancy.