The 26S proteasome is the key enzyme of the ubiquitin-dependent pathway of protein degradation. This energy-dependent nanomachine is composed of a 20S catalytic core and associated regulatory complexes. The eukaryotic 20S proteasomes demonstrate besides several kinds of peptidase activities, the endoribonuclease, protein-chaperone and DNA-helicase activities. Ubiquitin-proteasome pathway controls the levels of the key regulatory proteins in the cell and thus is essential for life and is involved in regulation of crucial cellular processes. Proteasome population in the cell is structurally and functionally heterogeneous. These complexes are subjected to tightly organized regulation, particularly, to a variety of posttranslational modifications. In this review we will summarize the current state of knowledge regarding proteasome participation in the control of cell cycle, apoptosis, differentiation, modulation of immune responses, reprogramming of these particles during these processes, their heterogeneity and involvement in the main levels of gene expression.