Colorectal cancer (CRC) is the third most common cancer worldwide. Traditionally chemotherapy for CRC is mainly targeting on inducing apoptosis. However, the chemo-resistant and defective in apoptosis induction has become prevalent. Thus, it may have important therapeutic implications to exploit novel anticancer drugs to trigger non-apoptotic programmed cell death. Indeed, non-apoptotic cell death is considered a novel strategy to overcome drug resistance, because in most cases drug resistance results from evasion and insensitivity to apoptosis. Currently, accumulating evidence shows that phytochemicals with diverse chemical structures and pharmacological effects serve as safe and effective agents against drug resistance via triggering non-apoptotic cell death in cancer cells. In this concise chapter, we summarize the developments of non-apoptotic cell death triggering by phytochemicals in cancer cells. Understanding the role of phytochemicals in regulating non-apoptotic cell death will provide prospective strategies for cancer resistant therapy, with a focus on CRC.