Colorectal cancer (CRC) is one of the most common cancers worldwide with a high incidence and mortality rate. Integrative studies including systematic sequencing of colorectal tumors have provided an unprecedented insight into the molecular basis of CRC. Recently, evidence indicates that F-box proteins (FBPs) play a critical role in the oncogenesis, invasion, metastasis and prognostic assessment of CRC. Therefore, this review discusses the recent literature regarding the function and regulation of FBPs in the pathogenesis of CRC. Furthermore, we highlight that FBPs may represent an attractive therapeutic target for CRC.