RATIONALE: One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer's disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. OBJECTIVE: The aim of this review was to provide an overview of the effects of phosphodiesterase inhibitors (PDE-Is) on cognition, the possible underlying mechanisms, and the relationship to current theories about memory formation. MATERIALS AND METHODS: Studies of the effects of inhibitors of different PDE families (2, 4, 5, 9, and 10) on cognition were reviewed. In addition, studies related to PDE-Is and blood flow, emotional arousal, and long-term potentiation (LTP) were described. RESULTS: PDE-Is have a positive effect on several aspects of cognition, including information processing, attention, memory, and executive functioning. At present, these data are likely to be explained in terms of an LTP-related mechanism of action. CONCLUSION: PDE-Is are a promising target for cognition enhancement; the most suitable candidates appear to be PDE2-Is or PDE9-Is. The future for PDE-Is as cognition enhancers lies in the development of isoform-specific PDE-Is that have limited aversive side effects.