Phosphodiesterase 4 (PDE4) is member of the growing family of proteins that regulate the intracellular concentrations of cyclic AMP and cyclic GMP. Earliest described inhibitors of PDE4, such as rolipram, demonstrate marked anti-inflammatory and bronchodilatory effects in vitro and in vivo. The clinical utility of these earlier compounds was limited by their propensity to elicit gastrointestinal side effects. This has led to an extensive effort to identify novel PDE4 inhibitors that maintain the anti-inflammatory activity and bronchodilatory activity of rolipram but with a reduced potential to produce side effects. This article summarizes the evidence supporting the utility of selective PDE4 inhibitors in the treatment of asthma and chronic obstructive pulmonary disease, discusses the recent results obtained in clinical trials with second-generation inhibitors, and presents two approaches designed to identify additional novel selective PDE4 inhibitors.