Few of the more than 65,000 chemicals listed in the Environmental Protection Agency (EPA) inventory have been tested for neurotoxicity. The nervous system may be especially vulnerable to toxicants because many compounds can cross the blood-brain barrier and induce irreversible damage. Additionally, the young, the elderly, and other sensitive populations may be particularly susceptible to neurotoxic injury. The EPA has developed guidelines including neurobehavioral, neuropathological, and neurochemical tests for the identification of possible neurotoxicants. In the present review, tests included in the current EPA guidelines for neurotoxicity testing are described and evaluated. The main benefit of the tests is that regulators are familiar with them, thus facilitating interpretation. Additionally, validation data on these tests are available for many known neurotoxicants. These factors make it difficult to introduce new methods that may include in vitro and other techniques. The current in vivo tests can be costly and prolonged and can involve the use of many laboratory animals, making them inappropriate for generalized use on existing chemicals. It is suggested that alternative tests be incorporated for screening of large numbers of chemicals and that testing priority be given to chemicals on the basis of structure/ activity relationships, lipophilicity, bioaccumulation, and extent of exposure.