Colorectal cancer is the second most common cause of cancer-related death. A significant obstacle to successful management of patients with colorectal cancer is intrinsic drug resistance or, in patients who initially responded to chemotherapy, acquired drug resistance. Failure in normal apoptotic pathways often contributes to resistance to anticancer drugs or radiotherapy. As a result, the identification of genes that control cell death and apoptosis has come to the forefront of cancer research, leading to new targets and novel therapeutic strategies in the treatment of colorectal cancer. To this effect, the authors have recently identified a new apoptotic signaling pathway that occurs through the transcription factor interferon regulatory factor-5. Here, the different strategies for targeting the interferon regulatory factor-5 signaling pathway in colorectal cancer are discussed. These strategies can be applied to a new generation of cytotoxic agents, as well as to novel biological compounds that are directed at inducing and/or activating interferon regulatory factor-5 or key components of this pathway.