The ubiquitin–proteasome system of intracellular proteolysis is essential for cell viability. We propose the concept that neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other conditions including some types of cancer, collectively represent a raft of ‘ubiquitin protein catabolic disorders’ in which altered function of the ubiquitin–proteasome system can cause or directly contribute to disease pathogenesis. Genetic abnormalities within the ubiquitin pathway, either in ubiquitin‐ligase (E3) enzymes or in deubiquitinating enzymes, cause disease because of problems associated with substrate recognition or supply of free ubiquitin, respectively. In some cases, mutations in protein substrates of the ubiquitin–proteasome system may directly contribute to disease progression because of inefficient substrate recognition. Mutations in transcripts for the ubiquitin protein itself (as a result of ‘molecular misreading’) also affect ubiquitin‐dependent proteolysis with catastrophic consequences. This has been shown in Alzheimer's disease and could apply to other age‐associated neurodegenerative conditions. Within the nervous system, accumulation of unwanted proteins as a result of defective ubiquitin‐dependent proteolysis may contribute to aggregation events, which underlie the pathogenesis of several major human neurodegenerative diseases.