Phosphodiesterase enzymes (PDE) have long been known as regulators of cAMP and cGMP, second messengers involved in various signaling pathways and expressed in a variety of cell types implicated in respiratory diseases such as airway smooth muscle and inflammatory cells making them a key target for the treatment of lung diseases as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and pulmonary hypertension (PH). The first reported PDE inhibitor was the xanthine, theophylline, described as a non-specific PDE inhibitor and whilst this drug is effective, it also has a range of unwanted side effects. In an attempt to improve the therapeutic window of xanthines, a number of selective PDE inhibitors have been developed for the treatment of respiratory diseases with only the selective PDE 4 inhibitor, roflumilast, being approved for the treatment of severe COPD. However, roflumilast also has a very narrow therapeutic window due to a number of important doses limiting side effects, particularly in the gastrointestinal tract. However, there continues to be research carried out in this field to identify improved selective PDE inhibitors, both by targeting other PDE subtypes (e.g., PDE 7 found in a number of inflammatory and immune cells) and through development of selective PDE inhibitors for pulmonary administration to reduce systemic exposure and improve the side effect profile. This approach has been exemplified by the development of ensifentrine, a dual PDE 3-PDE 4 inhibitor, an inhaled drug that has recently completed two successful Phase III clinical trials in patients with COPD.