Proteins are essential cellular components involved in diverse biological processes, from enzymatic catalysis and hormone regulation to structural support and immune response. Proteostasis is vital for healthy brain function and is particularly important in post-mitotic neurons that cannot readily replace damaged proteins due to their limited ability to divide. The ubiquitin-proteasome system (UPS) plays a central role in maintaining this balance by selectively degrading misfolded or damaged proteins and conducting the turnover of proteins according to cellular requirements. The UPS is a highly regulated, adenosine triphosphate-dependent pathway that targets proteins for degradation by the 26S proteasome. This process involves ubiquitination, the covalent attachment of ubiquitin chains to target proteins, marking them for destruction. The specificity of the UPS is conferred by hundreds of E3 ubiquitin ligases, which recognize specific substrates and are involved in various cellular processes. In this chapter, we are discussing about the requirement of UPS in cellular physiology.