RING-in-between-RING (RBR) E3 ligases are one class of E3 ligases that is characterized by the unique RING-HECT hybrid mechanism to function with E2s to transfer ubiquitin to target proteins for degradation. Emerging evidence has demonstrated that RBR E3 ligases play essential roles in neurodegenerative diseases, infection, inflammation and cancer. Accumulated evidence has revealed that RBR E3 ligases exert their biological functions in various types of cancers by modulating the degradation of tumor promoters or suppressors. Hence, we summarize the differential functions of RBR E3 ligases in a variety of human cancers. In general, ARIH1, RNF14, RNF31, RNF144B, RNF216, and RBCK1 exhibit primarily oncogenic roles, whereas ARIH2, PARC and PARK2 mainly have tumor suppressive functions. Moreover, the underlying mechanisms by which different RBR E3 ligases are involved in tumorigenesis and progression are also described. We discuss the further investigation is required to comprehensively understand the critical role of RBR E3 ligases in carcinogenesis. We hope our review can stimulate the researchers to deeper explore the mechanism of RBR E3 ligases-mediated carcinogenesis and to develop useful inhibitors of these oncogenic E3 ligases for cancer therapy.