The regulation of apoptosis (programmed cell death) has been the subject of a vast body of research because of its implications in normal development, tissue homeostasis and a wide range of diseases. The ubiquitin-proteasome system (UPS) plays a prominent role in the control of apoptosis by targeting key cell death proteins, including caspases, the central executioners of apoptosis. Here we summarize the major findings on the function of the UPS in both pro- and anti-apoptotic regulation.