Bronchial asthma, a complex multifactorial disease related to the respiratory system, is characterized by hyperactivity of the respiratory tract to external stimuli such as cold or warm or moist air, exercise, exertion, and emotional stress. Under this condition the airway occasionally constricts, becomes inflamed, and is lined with excessive amounts of mucus. This airway narrowing and inflammation lead to a number of severe lung diseases including asthma and chronic obstructive pulmonary diseases (or COPD, also known as chronic obstructive airway disease, chronic obstructive lung disease, or chronic airflow limitation and chronic airflow obstruction). The airflow limitation is usually progressive and associated with abnormal inflammatory response of the lungs to noxious particles or gases. COPD and asthma, a major public health burden worldwide, are reported to be causing the deaths of more than 250 000 people every year according to the latest WHO statistics (2007). COPD is projected to be the third leading cause of death by 2020. The estimation that 300 million people worldwide have asthma and 210 million people have COPD highlights the continued need for improved therapies. Bronchodilator drugs are currently the preferred choice for the symptomatic management of COPD, as they are more effective and have fewer side effects. However, these agents do not address the underlying chronic inflammation or the changes in airway structure. While the introduction of more effective treatments and the use of nonpharmacological interventions, such as pulmonary rehabilitation and noninvasive ventilation (NIV), have improved the management of COPD considerably,1 no existing therapies have been shown to reduce the disease progression (via limiting or preventing the progressive and destructive changes of airways observed in COPD). Notably, among the new anti-inflammatory agents currently being developed, phosphodiesterase 4 (PDE4) inhibitors proved to be very effective in attenuating the responses of various inflammatory cells through their ability to elevate cyclic 3′,5′-adenosine monophosphate (cAMP) levels. This review highlights the design and structure-activity relationships of the PDE4 inhibitors for oral and inhaled delivery reported over the past 10 years along with the status of advanced clinical candidates. Also, an attempt was made to mainly cover the PDE4 inhibitors reported in various scientific journals rather than in patent literature.