<p>The multi-stage cascade impactor (CI) is the recognized apparatus for the characterization of the aerodynamic particle size distribution (APSD) of aerosols emitted from all classes of orally inhaled products. There is presently a mixed level of understanding in the community of those evaluating inhaler performance about the fundamentals of how these apparatuses accomplish their particle size fractionation and therefore how to analyze their data in a technically correct and meaningful manner. The purpose of this article, therefore, is first to set out how the CI functions from the standpoint of the underlying physical processes associated with inertial size fractionation. The explanation of these size fractionation processes describes the relationship of the mass of active pharmaceutical ingredient to particle aerodynamic size. Second, based on these fundamentals, a detailed analysis is provided in support of calculating in a technically correct manner the cascade impactor-derived estimation of metrics describing the APSD. In a comprehensive Supplemental Information packet, the underlying mathematical principles are explained that govern both arithmetic and geometric forms of the traditional assumed shapes that the APSD may take when deriving measures in support of inhaler performance assessments.</p> Graphical Abstract <p></p>