Behavioral experience (BE) can critically influence later behavior and brain function, but the central nervous system (CNS) consequences of most developmental neurotoxicants are examined in the absence of any such context. We previously demonstrated marked differences in neurotransmitter changes produced by developmental lead (Pb) exposure ± prenatal stress (PS) depending upon whether or not rats had been given BE (Cory-Slechta, D. A., Virgolini, M. B., Rossi-George, A., Weston, D., and Thiruchelvam, M. (2009). The current study examined the hypothesis that the nature of the BE itself would be a critical determinant of outcome in mice that had been continually exposed to 0 or 100 ppm Pb acetate in drinking water alone or in combination with prenatal restraint stress. Half of the offspring in each of the four resulting groups/gender were exposed to positively reinforced (food-rewarded Fixed Interval schedule-controlled behavior) or negatively reinforced (inescapable forced swim) BE. Brain monoamines and amino acids differed significantly in relation to BE, even in control animals, as did the trajectory of effects of Pb ± PS, particularly in frontal cortex, hippocampus (both genders), and midbrain (males). In males, Pb ± PS-related changes in neurotransmitters correlated with behavioral performance. These findings suggest that CNS consequences of developmental toxicants studied in the absence of a broader spectrum of BEs may not necessarily be predictive of human outcomes. Evaluating the role of specific BEs as a modulator of neurodevelopmental insults offers the opportunity to determine what specific BEs may ameliorate the associated impacts and can assist in establishing underlying neurobiological mechanisms.