Cilomilast (Ariflo, SB 207499) is an orally active, second-generation phosphodiesterase (PDE) 4 inhibitor that is being developed by GlaxoSmithkline for the treatment of chronic obstructive pulmonary disease (COPD). The results of Phase I and Phase II studies have demonstrated that cilomilast significantly improves lung function and quality of life to a clinically meaningful extent, which has led to a comprehensive Phase III programme of research evaluating efficacy, safety and mechanism of action. However, the results of those Phase III studies are unremarkable and disappointing, raising doubt over the future of cilomilast as a novel therapy for COPD. This review summarizes data obtained from the Phase III clinical development programme, highlights some of the potential concerns both specific to cilomilast and to PDE4 inhibitors in general and assesses the likelihood that cilomilast will reach the market.