Gastric cancer (GC) is one of the commonest cancers with high mortality. Despite improvement in early detection and treatments, the outcome of advanced GC remains unsatisfactory due to the poor understanding of the intricate pathogenesis of GC. GC is a multifactorial and multistep disease which involves activation of oncogenes and inactivation of tumor suppressor genes. Ubiquitin proteasome system (UPS) catalyzing many critical protein substrates is involved in initiation and development of cancer. F-box proteins (FBPs) are the main functional components of UPS. Accumulated evidence strongly suggests that abnormal regulations of FBPs contribute to uncontrolled proliferation, genomic instability and cancer. In this review, we discuss how the dysregulated FBPs promote the occurrence and development of GC.