Proteasomes are highly conserved multienzyme complexes responsible for the proteolytic degradation of short-lived, regulatory, misfolded, and damaged proteins. They play an important role in the processes of brain plasticity, and the decrease in their function is accompanied by the development of neurodegenerative pathology. Studies performed in different laboratories both on cultured mammalian and human cells and on preparations of the rat and rabbit brain cortex revealed a large number of proteasome-associated proteins. Since the identified proteins belong to certain metabolic pathways, multiple enrichment of the proteasome fraction with these proteins indicates their important role the proteasome functioning. Extrapolation of the experimental data, obtained on various biological objects, to the human brain, suggests that proteasome-associated proteins account for at least 28% of the human brain proteome. The proteasome interactome of the brain contains a large number of proteins involved in the assembly of these supramolecular complexes, regulation of their functioning, and intracellular localization, which can be changed at different conditions (for example, during oxidative stress) or in different phases of the cell cycle. In the context of the molecular functions of the Gene Ontology (GO) Pathways, the proteins of the proteasome interactome mediate cross-talk between components of more than 30 metabolic pathways annotated in terms of GO. The main result of these interactions is the binding of adenine and guanine nucleotides, crucial for realization of the nucleotide-dependent functions of the 26S and 20S proteasomes. Since the development of neurodegenerative pathology is often associated with a regioselective decrease in the functional activity of proteasomes, a positive therapeutic effect will obviously be provided by factors increasing the proteasomal activity. In any case, the pharmacological regulation of brain proteasomes seems to be realized through changes in the composition and/or activity of proteins associated with proteasomes (deubiquitinase, PKA, CaMKIIα, etc.).