In response to environmental stimuli, cells make a series of adaptive changes to combat the injury, repair the damage, and increase the tolerance to the stress. However, once the damage is too serious to repair, the cells will undergo apoptosis to protect the overall cells through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions to form protein aggregation, which may ultimately produce serious damage to the cells. Ubiquitin plays an important role in the degradation of these unnatural proteins by tagging with ubiquitin chains in the ubiquitin–proteasome or autophagy system. If the two processes fail to eliminate the abnormal protein aggregates, the cells will move to apoptosis and death. Dysregulation of ubiquitin–proteasome system (UPS) and autophagy may result in the development of numerous diseases. This review focuses on the molecular mechanisms of UPS and autophagy in clearance of intracellular protein aggregates, and the relationship between dysregulation of ubiquitin network and diseases.