The role of F-box proteins in pancreatic tumorigenesis is emerging owing to their pivotal and indispensable roles in cell differentiation, cell cycle regulation and proliferation. In this review, we will focus on β-TrCP (β-transducin repeat-containing protein) and two other prototypical mammalian F-box proteins, Fbxw7 and Fbxw8, in pancreatic tumorigenesis and progression. We will highlight the functions and regulation of these F-box proteins, their respective substrates and cross-talks with other key signaling pathways, such as the Ras-Raf-Mek-Erk, Hedgehog, NFκB, TGF-β, Myc and HPK1 signaling pathways in pancreatic cancer.