The Ubiquitin-Proteasome System (UPS) eliminates unwanted or misfolded proteins in cells. The proteins are post-translationally modified with ubiquitin and subsequently degraded by the proteasome. The UPS has been targeted in different ways for cancer therapy. These include several frontline cancer therapies, including proteasome inhibitors such as bortezomib, which block the proteolytic activity of the 20S proteasome core, and immunomodulatory drugs (IMiDs) such as thalidomide and lenalidomide, which function as molecular glue degraders by promoting protein degradation via the UPS. While many components of the UPS are individually being explored as direct anti-cancer targets, in recent years the UPS has been increasingly co-opted for targeted protein degradation to eliminate oncoproteins via heterobifunctional PROteolysis Targeting Chimera (PROTAC) molecules. In this review, we describe the various concepts of targeting the UPS for cancer therapy. We describe the advances made in hijacking the UPS for targeted protein degradation. Particular emphasis is placed on the development of PROTAC molecules currently in clinical pipelines that target relevant oncoproteins. We also discuss emerging heterobifunctional induced-proximity modalities beyond PROTACs that seek to modulate post-translational modifications on target proteins to rewire cell signaling, potentially offering novel anti-cancer therapeutic opportunities.