Protein-homeostasis (proteostasis) is a natural phenomenon that maintains the turnover of proteins in an organism. The turnover includes synthesis, modification of proteins, and degradation of the damaged or misfolded ones to maintain cellular integrity. These processes are temporally and spatially regulated. Proteins regulate cellular functions and share integrated networks with other cellular components. Therefore, their formation and degradation must be systematically regulated; otherwise, failure of proteostasis results in cellular dysfunction. It may lead to ageing and neurodegenerative disorders (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases (like Creutzfeldt-Jakob disease). Loss of the proteostasis system includes accumulation and misfolding of proteins inside the cell, leading to initiation and progression of cellular stress and eventually to cell death. Proteostasis is maintained by the cellular machinery of molecular chaperones, other proteolytic pathways, and autophagy. In this chapter, we have explored the proteostasis system and networks involved in driving cellular integrity and how the fault in the machinery leads to the malfunctioning of biochemical pathways at a cellular level and various physiological and cognitive anomalies. Various components of proteostasis have been identified as potential targets for therapeutic intervention to attain healthy ageing and reduce pathological symptoms of neurodegenerative disorders.