Phosphodiesterase-4 (PDE4) is a low K m, cyclic AMP-selective phosphodiesterase (PDE) that is highly expressed in the central nervous system (CNS), including regions involved in the regulation of affective behavior, mood, and cognition. 1,2 Interest in its potential as a target for psychopharmacological medications began in the early 1980s with the seminal work of Wachtel that described the behavioral effects of the prototypic PDE4 inhibitor rolipram and demonstrated its activity in preclinical models sensitive to antidepressant drugs. 3,4 540Subsequent work demonstrated that rolipram has effects in cognitive models, antagonizing the amnesic effects of scopolamine. 5,6 Overall, this research provided an impetus for examining the potential of PDE4 inhibitors for treating depression and neuropsychiatric illnesses that involve some measure of cognitive impairment. While progress has been made in elucidating the neurochemical and molecular mechanisms that underlie the various behavioral effects of PDE4 inhibitors, it has become apparent that drug development in this area is quite challenging, in part due to an incomplete understanding of the function and regulation of PDE4 in neurons. As a consequence of this, it has proven difficult to use neurochemical and molecular indices of inhibitor interaction to predict the pattern of behavioral effects related to antidepressant and procognitive efficacy relative to side effects such as nausea, emesis, and sedation.