Well-respected leaders in the field of in vitro neurotoxicology take a fresh look at their own and other's work, critically and comparatively analyzing it across experimental systems and toxicants, and synthesizing essential principles for in vitro neurotoxicity testing. Neurotoxicants of significance to human health are emphasized, especially those for which metabolism and dose-responses are well well studied both in vivo and in vitro: lead, mercury, organophosphorous insecticides, polychlorinated biphenyls and dioxin, ethanol, and endogenous proteins. The goal is to set out new concepts and research directions that will hasten significant improvement in the methods and systems for in vitro neurotoxicity testing.