<p>F-box proteins have been well-established as important regulators of cancer development after decades of exploration. As the understanding of cancer biology continues to deepen, novel biological characteristics of cancer cells have been incorporated, and the perspective has expanded from cancer cells themselves to a more complex tumor microenvironment (TME). In this context, F-box proteins form an extensive and multi-layered regulatory network to fine-tune diverse biological events, not only within cancer cells, but also in the TME. Therefore, in this review, we summarize the functional and mechanistic paradigms of F-box proteins in both cancer cells and the TME, and underscore their adaptability and wide coverage on the basis of a sophisticated regulatory hierarchy, presenting the clinical prospects of F-box proteins as potential targets for cancer therapy.</p>