Thus, the present review was conducted to address the following questions: (1) which members of the NEDD4 E3 ligase family are implicated in defective autophagy in cancer cells?, (2) which types of cancers are affected?, (3) what is their activity in autophagy in different cancer cells; autophagy inhibitor or autophagy inducer and tumor promoter or tumor suppressor ?, (4) what are their new substrates and molecular mechanisms underlying their effects?, (5) How can they be targeted to conquer different cancers?. Here, NEDD4 is linked to cancer.