Proteostasis, the maintenance of protein homeostasis within cells, is crucial for cellular function and organismal health. Disruption of proteostasis is implicated in various neurodegenerative diseases (NDDs), cancer, and aging. The molecular dynamics of proteostasis mechanisms and their implications for neurodegenerative diseases can be Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s diseases (HD). This chapter explores the genetic underpinnings of proteostasis disruption, focusing on the interplay between key genetic factors and protein quality control mechanisms. We discuss how mutations in genes encoding chaperones, proteases, and components of the ubiquitin-proteasome and autophagy-lysosome systems can lead to proteostasis imbalance. Furthermore, we examine the role of genetic variations in modulating protein folding, aggregation propensity, and clearance kinetics. Insights from genome-wide association studies (GWAS) and functional genomics approaches shed light on the genetic architecture of proteostasis-related traits and disease susceptibility. Finally, we discuss emerging therapeutic strategies targeting genetic determinants of proteostasis disruption, highlighting the potential for precision medicine interventions to restore protein homeostasis and ameliorate disease phenotypes. This comprehensive overview provides understanding of the genetic basis of proteostasis directive and its suggestions for human health and disease.