Phosphodiesterases (PDE) are a family of enzymes responsible for the metabolism of the intracellular second messengers cyclic AMP and cyclic GMP. PDE4 is a cyclic AMP specific PDE that is the major if not sole cyclic AMP metabolizing enzymes found in inflammatory and immune cells, and contributes significantly to cyclic AMP metabolism in smooth muscles. Based on its cellular and tissue distribution and the demonstration that selective inhibitors of this isozyme reduce bronchoconstriction in animals and suppress the activation of inflammatory cells, PDE4 has become an important molecular target for the development of novel therapies for asthma and COPD. This chapter will review the evidence demonstrating the ability of PDE4 inhibitors to modify airway obstruction, airway inflammation and airway remodelling and hyperreactivity, will present some preliminary findings obtained with theses compounds in clinical trials and and will discuss experimental approaches designed to identify novel compounds that maintain the beneficial activity of the initial selective PDE4 inhibitors but with a reduced tendency of elicit the gastrointestinal side effects observed with this class of compounds.