To address the growing need for scientifically valid and humane alternatives to developmental neurotoxicity testing (DNT), we propose that basic research scientists in developmental neurobiology be brought together with mechanistic toxicologists and policy analysts to develop the science and policy for DNT alternatives that are based on evolutionarily conserved mechanisms of neurodevelopment. In this article we briefly review in vitro and other alternative models and present our rationale for proposing that resources be focused on adapting alternative simple organism systems for DNT. We recognize that alternatives to DNT will not completely replace a DNT paradigm that involves in vivo testing in mammals. However, we believe that alternatives will be of great value in prioritizing chemicals and in identifying mechanisms of developmental neurotoxicity, which in turn will be useful in refining and reducing in vivo mammalian tests for exposures most likely to be hazardous to the developing human nervous system.