Aerosol delivery represents a rapid and non-invasive way to directly reach the lungs while escaping the hepatic first-pass effect. The development of pulmonary drugs for respiratory diseases such as cystic fibrosis, lung infections, pulmonary fibrosis or lung cancer requires an enhanced understanding of the relationships between the natural physiology of the respiratory system and the pathophysiology of these conditions. This knowledge is crucial to better predict and thereby control drug deposition. Moreover, aerosol administration faces several challenges, including the pulmonary tract, immune system, mucociliary clearance, the presence of fluid on the airway surfaces, and, in some cases, bacterial colonisation. Each of them directly influences on the bioavailability of the active molecule. In addition to these challenges, particle size and the device used to administer the treatment are critical factors that can significantly impact the biodistribution of the drugs. Nanoparticles are very promising in the development of new formulations for aerosol drug delivery, as they can be fine-tuned to reach the entire pulmonary tract and overcome the difficulties encountered along the way. However, to properly assess drug delivery, preclinical studies need to be more thorough to efficiently enhance drug delivery.