Inhibition of one or more members of the phosphoinositide 3-kinase (PI3K) family for the treatment of respiratory diseases remains the goal of many pharmaceutical companies over the past 20 years. Here we briefly review the PI3K family, then focus on the assessment of each isoform as a drug discovery target. The rationale for PI3Kα inhibition in the treatment of lung cancer, and PI3Kβ inhibitors in pulmonary thrombotic processes, are balanced with a potential side effect profile affecting metabolism and/or foetal development. Roles for PI3Kδ in inflammatory lung diseases and PI3Kγ in asthma are weighed against the consequences of manipulating key immune cell populations. We also discuss the current status and future potential of PI3K inhibitors in respiratory disease.