Cellular proteostasis is defined as an integrated approach of the cell to maintain a dynamic balance of healthy proteins. The term “proteostasis” brings in all the cellular acts of balancing among various aspects of a protein’s life, including but not limited to synthesis, folding, refolding, transport, and degradation. Among all these, protein degradation holds an important role as cells use this as a last resort to deal with faulty proteins. Old or misfolded proteins are subjected to degradation using a tightly regulated pathway. The ubiquitin-proteasome system (UPS) is an important machinery that cleaves long proteins into smaller oligopeptides using a multi-enzyme reaction that attaches ubiquitin (Ub) molecules to the substrates before targeting those to the proteasome. Genetic mutations, intra- or extracellular stresses, and pathological conditions may lead to an inefficient UPS, which may lead to aggravated proteotoxicity inside the cells. Altered proteostasis may lead to a large number of diseases collectively referred to as proteinopathies. The most prominent examples of this class are neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and so on. In this chapter, we discuss the roles of UPS in maintaining cellular proteostasis. We will briefly discuss the interplay between UPS and other proteostasis pathways, such as molecular chaperones and autophagy. Overall, the chapter advances our understanding of how deregulated UPS or overburdened proteasomes can lead to neurodegeneration.