Rectal cancer includes a wide range of diseases that require personalized treatments for optimization of results. Colorectal cancer is one of the best characterized for the genetic events underlying the development of malignancy. Most colorectal carcinomas develop from benign preneoplastic lesions; progression from benign adenoma to malignant carcinoma advances throughout a series of well defined histological stages of the adenoma-carcinoma sequence. The etiology of colorectal cancer is multifactorial with the participation of environmental factors, genetic susceptibility and somatic mutations during onset and progression. Molecular parameters of specific tumors can be predictive of therapeutic outcome or prognostic of the individual natural history. Main biological factors and their mechanisms of action in terms of response to therapies and late outcome, are illustrated.