Pb (lead) exposure and stress are co-occurring risk factors (particularly in low socioeconomic communities) that also act on common biological substrates and produce common adverse outcomes, including cognitive impairments. This study sought to determine whether lifetime Pb exposure combined with prenatal stress would enhance the cognitive deficits independently associated with each of these risk factors and to explore associated mechanisms of any observed impairments. Learning was evaluated using a multiple schedule of repeated learning and performance in female rats subjected to lifetime Pb exposure (0 or 50 ppm Pb in drinking water beginning in dams 2 months prior to breeding; blood Pb levels ∼10 μg/dl), to prenatal restraint stress on gestational days 16 and 17, or to both. Blood Pb, corticosterone levels, brain monoamines, and hippocampal nerve growth factor levels were also measured. Sequence-specific learning deficits produced by Pb, particularly the number of responses to correctly learn response sequences, were further enhanced by stress, whereas performance measures were unimpaired. Statistical analyses indicated significant relationships among corticosterone levels, frontal cortex dopamine (DA), nucleus accumbens dopamine turnover, and total responses required to learn sequences. This study demonstrates that Pb and stress can act together to produce selective and highly condition-dependent deficits in learning in female rats that may be related to glucocorticoid-mediated interactions with mesocorticolimbic regions of brain. These findings also underscore the critical need to evaluate toxicants in the context of other risk factors pertinent to human diseases and disorders.