Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.