Aerosolized drugs are universally used for treatment of cystic fibrosis airway disease. Inhalation can increase topical efficacy and reduce systemic exposure and toxicity of many drugs. A wide variety of inhaled drugs already exist with many more in the therapeutic pipeline. Understanding the principles of aerosol delivery and how aerosol devices function is important in designing the best therapeutic regimens for CF patients. The variables that determine where an aerosol deposits are numerous and complex. Important aerosol-related variables include particle-size distribution, hygroscopic properties, viscosity and surface tension of the drug. Patient-related variables include inspired flow rate, tidal volume, respiratory rate, breath-holding, upper airway anatomy, lower airways obstruction, and the cognitive and physical ability to use the device. These factors vary widely between patients of different age groups and disease severities, and cause the high variability in drug delivery seen with aerosol drugs. Classic aerosol delivery devices like metered dose inhalers and dry-powder inhalers are small, portable, and have short treatment times. However, they are limited by small drug payloads and user technique problems. Jet nebulizers are commonly used for CF drugs, are easy to operate, require no special breathing pattern, and can deliver very large quantities of drug. However, they require a power or air source, cleaning and sanitizing, and are relatively time consuming. Recently, novel aerosol delivery systems and formulations have been developed to improve delivery efficiency and reduce variability and delivery time. These new systems can ease the treatment burden and improve adherence and outcomes in cystic fibrosis. Pediatr Pulmonol. 2008; 43:S5–S17. © 2008 Wiley-Liss, Inc.