Colorectal cancer is the fifth common cancer in men and the third in women in Iran. There is no therapeutic approach for metastatic colorectal cancer, so it is imperative to identify new chemotherapeutic and molecular targets to improve patient’s survival and the probability of being cured. Resistance to apoptosis plays an important role in the development and progression of different cancers such as CRC. Understanding the basis of the mechanism of apoptosis pathways and the tools used by cancer for escaping from apoptosis results in the design of effecient therapies that inhibit cell growth. One of the apoptosis pathways is the extrinsic–Fas/FasL pathway. In this article, the extrinsic pathway of apoptosis with focus on death pathway of Fas and FasL in colorectal cancer has been reviewed aimed at finding new therapeutic targets for CRC. Fas-mediated apoptosis of lymphocytes normally serves immunoregulatory roles. Anti-tumor cytotoxic T cells and NK cells eliminate tumor cells by inducing Fas-mediated apoptosis using FasL. Cancer cells such as colon tumor cells enable a “Fas counterattack” against Fas sensitive antitumor lymphocytes and lead to immune suppression against tumor cells. This systematic review article was conducted by searching keywords; Cancer, Apoptosis, Fas, FasL, Immune system in valid sources. 86 studies analyzing apoptotic changes in cancer from 1995 to 2020 were selected and used. Fas counterattack is a mechanism, used by tumor cells to evade immune surveillance. It might be important to study the basis of this mechanism to design tumor-specific and effective treatment. Triggering Fas-mediated  apoptosis is an effective approach to cancer therapy. Altering the expression of Fas and FasL genes can inhibit the tumor strikes back by tumors and our immune system and work officially against tumor cells.