Methylphenidate (MPH), a dopamine reuptake inhibitor, is used increasingly to treat attention deficit and hyperactivity disorders in children. Given that dopaminergic mechanisms, contribute to the structural and functional maturation of brain circuitry, consideration of the potential influence of MPH in disrupting such processes seems warranted. Following a similar logic regarding the relevance of glutamate neurotransmission in mediating aspects of brain maturation, we and others have previously utilized in vivo and in vitro studies of the developing rodent brain to establish that MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist has both neuroprotective and pro-apoptotic actions. In this study we used a neonatal murine model of excitotoxin-induced cortical injury to compare such actions between MPH and MK-801, and found that MPH shared some biological properties with MK-801. Specifically, both drugs were neuroprotective against excitotoxic challenge resulting in neonatal brain lesions and in vitro neuronal death, but both drugs also exacerbated programmed neural cell death. However, this profile of action was not shared by the dopamine reuptake blocker GBR-12783, a molecule which like MPH binds to and blocks the dopamine transporter, but which is structurally dissimilar to MPH, suggesting that inhibition of dopamine reuptake alone cannot explain the results from our MPH studies. The implications of our findings are that when studied in our developmental mouse model both drugs demonstrate similar capacities to be either neuroprotective or pro-apoptotic, depending on the specific biologic setting in which they act. Additional studies to identify some potential positive as well as negative consequences of exposure to these drugs during brain development in clinical settings are warranted.