Of all known neurotoxicants, lead (Pb) has received by far the most research attention. Because of increasing awareness of its untoward effects, investigation of the metal’s central nervous system (CNS) actions has extended over several decades and across multiple experimental species, methods, and approaches. As a result, numerous actions of lead on the brain have been uncovered at the cellular and systems levels (e.g., ref. 1). Nonetheless, progress toward defining the specific bases of the neurotoxicity observed in exposed young children has been slow and inefficient and has not been commensurate with the magnitude of effort invested. Multiple factors have limited the development of this new information, but one of the most prominent has been the difficulty in linking findings obtained with in vitro approaches to neurotoxicity present in vivo.