Cyclic nucleotides are powerful signaling molecules and their sole means of removal is through the action of cyclic nucleotide phosphodiesterases (PDEs). Elevating levels of cAMP is beneficial in many diseases, including neurological conditions, cancers, viral infections and most inflammatory disorders. There are 11 known PDE families, with PDE4 being the most highly expressed. Evidence of the clinical usefulness of PDE4 inhibition has come from the use of specific chemical inhibitors and the generation of knock-out mice models. There exists an extensive range of PDE4 family members, because there are four subfamilies, each encoded by their own gene and each capable of generating multiple isoforms. Several members of the PDE4 family are found to be expressed in every cell and tissue studied and evidence is now being uncovered indicating unique functions for each. Their actions are controlled by their expression patterns, subcellular location and interaction with other signaling pathways. The first generation of PDE4 inhibitors, although potent anti-inflammatory agents, failed as pharmaceuticals owing to their emetic and gastric side-effects. A new generation of chemical inhibitors is now nearing the market, which display greatly reduced side-effects. In the future lies the generation of more specific inhibitors that will focus upon particular diseases. This will be achieved by targeting specific PDE4 family members. Because the current target of chemical inhibition (the catalytic site) is virtually identical between isoforms, this specificity is likely to be achieved by blocking the enzyme's interaction with other signaling cascades.