FBW7 (F-box and WD repeat domain-containing 7) has been characterized as an onco-suppressor protein in human cancers. Recent studies have also shown that FBW7 exerts its anti-tumor function primarily by promoting the degradation of various oncoproteins, through which FBW7 regulates cellular proliferation, differentiation and causes genetic instability. In this review, we will discuss the role of FBW7 downstream substrates and how dysregulation of Fbw7-mediated proteolysis of these substrates contributes to tumorigenesis. Additionally, we will also summarize the currently available various Fbw7-knockout mouse models that support Fbw7 as a tumor suppressor gene in the development and progression of human malignancies.