Neurodegenerative diseases are associated with progressive degeneration of neurons or death of nerve cells. This chapter emphasizes mainly on age-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Prion disease. Abnormal fibrous tangles, β sheet plaques, cholinergic deficits, chronic neuroinflammation, nerve cell death, oxidative stress, and inflammatory cascade are the common molecular and biochemical changes of Alzheimer’s disease. Aggregated neurofibrillary tangles and accumulated amyloid-beta(Aβ) are the defining pathological hallmarks of Alzheimer’s disease. Parkinson’s disease is a composite and multifactorial disease in which different factors concur with pathogenic factors. Prion disease is an infectious neurodegenerative disease characterized by misfolded prion protein accumulation in the brain and leads to nerve cell loss. Currently, different models have been established to understand the pathophysiology of these diseases and are also used to investigate new therapeutic compounds. Although various in-vivo models are used to study neurodegenerative diseases, in vitro models provide more insights on various pharmacological targets and mechanisms of disease during neurodegeneration. Human and animal cells derived cell cultures are used to study neurodegenerative diseases in order to accurately mimic brain environment and neuronal cell interactions. In vitro models show the reliable effect of compounds on various targets in the brain to study pathophysiological characteristics of the disease, and it also provides a controlled environment favourable to explore single pathogenic mechanisms. In this chapter, we discuss different in-vitro models used to study age-related neurodegenerative diseases.