Abstract: Targeted therapy is crucial for advanced colorectal cancer (CRC) with gene-positive drivers. With the development of deep sequencing technology, improvement in clinical tumor technology, and development of new targeted drugs, existing standard molecular pathological detection systems cannot meet the requirements of meticulous management of patients with advanced CRC. Rare gene mutations, amplifications, and rearrangements are associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare gene mutations in CRC to increase awareness and identify more accurate personalized treatments for these patients.