RNF43 (E3 ubiquitin-protein ligase RNF43 or RING-type E3 ubiquitin transferase RNF43) functions as a tumor suppressor, by exerting a predominant negative feedback mechanism in the Wnt/β-catenin signaling pathway. RNF43 inhibits Wnt/beta-catenin signaling by ubiquitinating Frizzled receptor and targeting it to the lysosomal pathway for degradation. Loss of function of RNF43 results in decrease/lack of degradation of Frizzled with enhancement of Wnt/β-catenin signaling pathway. Mutations of RNF43 have been reported in different cancers. We describe the structure of RNF43, its function and most frequent mutations in different cancers.