Second-order schedules of reinforcement model complex chains of responding for rewards such as food or drugs. Derived from studies of conditioned reinforcement, an important feature of these schedules is that responding is maintained by the response-dependent presentation of conditioned stimuli. They are thus well-suited to the study of the influences over drug seeking exerted by drug-associated stimuli. In the present review, we summarise studies investigating the neurobiology and neuropsychopharmacology of responding for cocaine under a second-order schedule of reinforcement. We conclude that limbic-striatal circuitries underlie drug seeking measured in this way. Emphasis is placed on potential interactions between structures within these subsystems by reviewing neuropsychopharmacological studies in which antagonists selective for either glutamate or dopamine receptors have been infused directly into limbic, cortical and striatal areas.