Inhalation of aerosolized pharmaceuticals is a non-invasive and convenient method of drug delivery typically used for local treatment of lung diseases. Large absorption area of the pulmonary region opens up the possibility of fast and effective transfer of inhaled medicines to the circulation in order to obtain systemic effects. This review is devoted to selected albeit essential challenges of targeting aerosolized drugs to the blood via the pulmonary part of the respiratory system. The special attention is given to some physicochemical aspects of drug formulation which are essential for overcoming the air-blood barrier present in the lungs. It is deemed that a careful analysis of multifarious physical and engineering problems, related to aerosol fate in the lungs, is indispensable for a better design of inhalation delivery systems for systemic drugs.