Abstract: Ubiquitin-proteasome system participates in the degradation of more than 80% of proteins in vivo and is involved in the regulation of cell proliferation, differentiation and survival. Therefore, dysregulations of this system result in pathologies including cancers. Accumulated evidence suggests that E3 ubiquitin ligases, which function actively in ubiquitin-proeasome system, play essential roles in cancer development. Moreover, great progress has been made in the research of Nedd4-like family of E3 ubiquitin ligases related to cancer. Because E3 Nedd4-likes modulate ubiquitination, lysosome or proteasome degradation, and nuclear translocation of diverse proteins, and they regulate important signaling pathways, such as TGFβ, EGF, IGF, VEGF, SDF-1, and TNFα, involved in tumorigenesis. In addition, several E3 Nedd4-likes directly modulate multiple cancer-related transcription factors, such as Smads, p53, KLF, RUNX, Jun, etc. Therefore, better insight of the oncogenic potential of these E3 Nedd4-likes may facilitate the identification and development of biomarkers and drug targets in human cancer. In this review, we provide a comprehensive summary of the characteristics, expression levels and molecular mechanisms of the Nedd4-like family of E3 ubiquitin ligases in human cancer.