Cyclic nucleotide phosphodiesterases (PDEs) are promising targets for pharmacological intervention. The presence of multiple PDE genes, diversity of the isoforms produced from each gene, selective tissue and cellular expression of the isoforms, compartmentation within cells, and an array of conformations of PDE proteins are some of the properties that challenge the development of drugs that target these enzymes. Nevertheless, many of the characteristics of PDEs are also viewed as unique opportunities to increase specificity and selectivity when designing novel compounds for certain therapeutic indications. This chapter provides a summary of the major concepts related to the design and use of PDE inhibitors. The overall structure and properties of the catalytic domain and conformations of PDEs are summarized in light of the most recent X-ray crystal structures. The distinctive properties of catalytic domains of different families as well as the technical challenges associated with probing PDE properties and their interactions with small molecules are discussed. The effect of posttranslational modifications and protein-protein interactions are additional factors to be considered when designing PDE inhibitors. PDE inhibitor interaction with other proteins needs to be taken into account and is also discussed.