Phosphodiesterase inhibitors (PDE-Is) are pharmacological compounds enhancing cAMP and/or cGMP signaling. Both these substrates affect neural communication by influencing presynaptic neurotransmitter release and postsynaptic intracellular pathways after neurotransmitter binding to its receptor. Both cAMP and cGMP play an important role in a variety of cellular functions including neuroplasticity and neuroprotection. This chapter provides a translational overview of the effects of different classes of PDE-Is on cognition enhancement in age-related cognitive decline and Alzheimer's disease (AD). The most effective PDE-Is in preclinical models of aging and AD appear to be PDE2-Is, PDE4-Is and PDE5-Is. Clinical studies are relatively sparse and so far PDE1-Is and PDE4-Is showed some promising results. In the future, the demonstration of clinical proof of concept and the generation of isoform selective PDE-Is are the hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-related cognitive decline and cognitive dysfunction in AD.