The importance of protein degradation for controlling individual protein levels is long beyond doubt. Yet only recent experimental evidence confirmed the key role of the ubiquitin–proteasome degradation pathway in the cell cycle, carcinogenesis, transcription, cell differentiation, tissue growth and atrophy, metabolism of various substrates, selective elimination of abnormal proteins, and antigen processing. The review considers the structures of the 26S proteasome and its 20S proteolytic core, the system of ubiquitination of proteins bearing a degradation signal, the role of the 26S proteasome in various metabolic processes, and possible mechanisms regulating the proteasomal activity in the cell.