There are a multitude of formulation factors to consider when developing a pMDI. Evaluation of each of these variables has been performed over the years, but there has been an abundance of different approaches in the determination of the effects on device performance. Thus, although much is known about pMDI on the empirical level, a systematic approach has clearly been missing. With the ratification of the Montreal Protocol and the introduction of alternative propellant systems, the opportunity to establish relationships between different levels of testing, such as in vitro measurements and in vivo outcomes, and in vivo assessments and clinical outcomes, has arrived. This review outlines research efforts that have focused on the formulation of propellant-driven metered dose inhalers using alternative propellants. These formulation factors, including device characteristics, are reviewed with respect to the performance of MDIs.