PD-1/PD-L1 blocking therapy is a new strategy for cancer treatment. In the past decade, PD-1/PD-L1 blocking therapy has been applied in a wide range of malignant tumors and achieved certain success. However, for colorectal cancer, only patients with deficiency mismatch repair (dMMR) and microsatellite instability high (MSI-H) have a positive response to PD-1/PD-L1 blocking therapy. Primary or acquired drug resistance may eventually lead to disease progression. Therefore, the resistance of PD-1/PD-L1 blocking therapy is still a major challenge hindering its further application. In order to overcome the resistance of blocking therapy, a large number of studies based on drug resistance mechanism have been carried out. In this review, we summarize the current status of PD-1/PD-L1 blocking therapy and explore the mechanism of drug resistance. The methods to reverse the drug resistance were prospected, hoping to improve the efficacy of PD-1/PD-L1 blocking therapy.