The ability to control the intracellular concentrations of proteins with small molecules has obvious implications for the treatment of cancer whose growth and spread is typically due to the dysregulation of just a small number of proteins. The ubiquitin proteasome system (UPS) is the tightly regulated machinery used by the cell to dispose of undesired proteins. We review herein how various components of the UPS can be targeted by small-molecule intervention to realize global or even specific control of protein levels. Building on the success that inhibitors of the proteasome have had in the clinic over the past decade, a growing number of clinical candidates directed at the UPS are currently being evaluated as cancer therapies.