Abstract Neoadjuvant chemoradiation is used as a preoperative standard treatment for the majority of patients with Stage II/III rectal cancers and, in attempt to facilitate surgical intervention, reduce the rate of local recurrence and improve overall outcomes in patients suffering from this malignancy. However, this modality results in a wide range of clinical responses. In many cases, a pathological complete response is achieved, while in others, receiving the same form of treatment, the tumor continues to grow. The specific phenotype of the tumor plays a major role in rendering tumor cells a survival advantage to the cytotoxic effects of chemoradiation. Several factors participating in proliferation, cell cycle, apoptosis and hypoxia have been investigated under a variety of conditions in pre-irradiated tissues and post-irradiated tumors. Mutations in the genes of these pathways have shown to lead to resistance to chemoradiation. This chapter describes colon cancer with emphasis on the molecular mechanisms that may lead to chemoradio-resistance of cells with cytotoxically induced DNA injury in rectal cancer.