Unwanted systemic absorption of drugs delivered for the local treatment of respiratory disease is well documented. Methods to minimize this now exist, especially for reduction of oropharyngeal deposition. While small molecules appear to be absorbed also from the airways, it is the alveolated regions that provide a large absorptive surface. Lung has been used as a portal for systemic delivery of substances such as anesthetics, nicotine and a number of illicit drugs. Much research has lead to the solutions of the fundamental technical hurdles of practicable delivery of systemic therapeutic drugs in milligram quantities to the lung efficiently and reproducibly. Commercial manufacturing processes exist for production of delivery systems suitable for this purpose. Generally, the deposition of small molecules in the "deep lung" leads to high absorption rates, making the inhalation delivery attractive for drugs with intended rapid onset of action. Many therapeutics, especially peptides and proteins, that cannot be delivered systemically non-invasively, are absorbed with various degrees of systemic bioavailability via inhalation. The critical factor for efficient and reproducible systemic delivery is lung deposition which depends on the properties of drug particles (size, shape, density, hygroscopicity, velocity, charge) and the state of the respiratory system (including the individual's anatomy, age, sex, disease, lung volume). While concerns exist about the potential adverse reactions of the immune system to therapeutic proteins and peptides delivered to and through the lung, there is not much data on the immune response or its link to any safety issues with inhaled biologics. Desirable systemic immune effects have been demonstrated by cytokine delivery to the lung.