This review presents the different pathways that nanomedicines can follow after deposition in the lung. These include their interactions with the air-liquid interface, their diffusion in and clearance with mucus, their uptake by lung-surface macrophages, their transport across respiratory epithelia and protein metabolism. These processes mostly occur simultaneously in the lung and their respective rates determine the dominant pathways followed by the particular nanomedicine. Accordingly, the fate of nanomedicines in the lung is highly dependent on the physico-chemical as well as biological properties of the compound considered. IgG are endocytosed by alveolar macrophages and transported across respiratory epithelia by receptor-mediated endocytosis while insulin is not taken up by alveolar macrophages and rapidly crosses the epithelium towards the systemic circulation via paracellular diffusion. Inhaled proteins are usually cleared from the lung within 24 h. Nanoparticles largely escape uptake by lung-surface macrophages and can remain in the lung for weeks, without significant translocation across respiratory epithelia. Major recent advances: The fate of therapeutic proteins within the lungs has been partly revealed over the past 15 years. Yet, many recent studies have investigated the pulmonary fate of nanoparticles and have highlighted their persistence within the lung, their low uptake by lung-surface macrophages and their limited translocation across respiratory epithelia towards the systemic circulation.