Behavior maintained under a differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, which reinforces responses with interresponse times greater than 72 s, exhibits a rather unique sensitivity to antidepressant drugs. Antidepressants from a number of pharmacological classes, including tricyclic antidepressants, selective serotonin or norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, as well as a number of atypical antidepressants and putative antidepressants, reduce response rate and increase reinforcement rate of rats under this schedule. These effects are observed acutely but persist or are augmented with repeated treatment. By contrast, drugs from a number of other psychotherapeutic classes do not, in general, produce similar effects. This includes anxiolytic, sedative, stimulant, opioid, antihistaminic, and anticholinergic drugs, which can produce false positive results in some preclinical tests for antidepressant efficacy. There are conflicting data regarding the utility of DRL behavior for discriminating the effects of antidepressant and antipsychotic drugs. This results in part from methodological differences among studies, but likely also reflects the overlap between the neuropharmacological and clinical effects of some antipsychotic and antidepressant drugs. DRL behavior also has proven useful for identifying neurochemical and neuroanatomical mediators of antidepressant effects on behavior. Consistent with clinical data, it appears that activation of noradrenergic or serotonergic systems provides for parallel means of producing antidepressant-like effects on DRL behavior. Finally, the results of studies using DRL behavior highlight important roles for central beta-1 adrenergic receptors, as well as 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors, in the mediation of antidepressant-like behavioral effects.