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To consider the lung as a target for drug delivery and to optimise strategies directed at the pulmonary route, it is essential to consider the role of pulmonary surfactant, a thin lipid–protein film lining the respiratory surface of mammalian lungs. Membrane-based surfactant multilayers are essential for reducing the surface tension at the respiratory air–liquid interface to minimise the work of breathing. Different components of surfactant are also responsible for facilitating the removal of potentially pathological entities such as microorganisms, allergens or environmental pollutants and particles. Upon inhalation, drugs or nanoparticles first contact the surfactant layer, and these interactions critically affect their lifetime and fate in the airways. This review summarises the current knowledge on the possible role and effects of the pulmonary surfactant system in drug delivery strategies. It also summarises the evidence that …