Phosphodiesterase-4 (PDE4) is a major cyclic AMP-hydrolyzing enzyme in inflammatory and immunomodulatory cells. The wide range of inflammatory mechanisms under control by PDE4 points to this isoenzyme as an attractive target for new anti-inflammatory drugs. Selective inhibitors of PDE4 have exhibited a broad spectrum of anti-inflammatory activities including the inhibition of cellular trafficking and microvascular leakage, cytokine and chemokine release from inflammatory cells, reactive oxygen species production, and cell adhesion molecule expression in a variety of in vitro and in vivo experimental models. The two main orally given PDE4 inhibitors are cilomilast and roflumilast with the latter to be considered more selective and potent with a greater therapeutic range. An additive suppressive effect on CD4 positive T-cells and dentritic cells suggests a immunomodulatory profile for these drugs. On the other hand, despite the above evidence, most of the clinical trials for both asthma and COPD do not provide strong evidence for clinical improvement with PDE4 inhibitors. Roflumilast has a better tolerability and safety profile with the main adverse events reported being nausea, diarrhea and abdominal pain. Interpretation of the up-to-date clinical results lead to a skepticism regarding the efficacy of the above drugs. This is partly supported by the fact that most of the clinical trials were presented in an abstract form and not as full paper data. Future studies and future evidence could answer whether PDE4 inhibitors represent an expensive designer theophylline or an effective anti-inflammatory drug with a strong place in guidelines. Pneumon 2006; 19(4):303-310. Key words: