The epidemic of neurodegenerative diseases, such as Alzheimer's disease, Parkinson’s disease, and cerebral ischemia (e.g., stroke), has long been a worldwide health and social concern with the rapid increase of aging population. To date, efficient therapeutic drugs are still insufficient, making the treatment of these diseases a big challenge to both basic researchers and clinical physicians. A few in vitro and in vivo experimental models are established to explore, as well as evaluate, protective and therapeutic agents. Among these models, cell-based screening models play an important role in the initial step of searching and identifying neuroprotective compounds. Primary cultured hippocampal and cortical neurons, as well as PC12 and SH-SY5Y cells, are among the frequently applied cells in these models. PC12 is an immortalized pheochromocytoma cell line that provides a series of classical screening models by applying a variety of neurotoxins, such as 6-hydroxydopamine, beta amyloid, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and paraquat, among others. In the present review, several neuroprotective and injury models induced by 4-hydroxynonenal, ethanol, high glucose, homocysteine, okadaic acid, rotenone, and oxygen-glucose deprivation, as well as documented protective agents, are discussed.