Pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD) are complex human airway diseases that affect millions of people worldwide. A topical drug delivery system such as a dry powder inhaler (DPI) is often used to deliver the drug directly to airways to increase the therapeutic index; however, accurately predicting the efficacy and pharmacokinetics of new molecular entities remains challenging, in particular, estimating the effective drug concentration at the site of action. This is of critical importance since many inhaled drugs are designed to have topical-only efficacy to reduce systemic side effects. Preclinically, drug delivery in rodents now focuses on mimicking the clinical dosing regimen, coupled with modeling approaches to better understand the lung PK/PD relationship. One modeling approach is the use of the systemic exposure to predict the drug concentration and release from the lung as the first step to model the lung PK/PD. With a tool compound, fluticasone propionate, the authors used a Loo-Riegelman-based pharmacokinetic analysis and compared several methods of dosing to rats to evaluate the suitability of using the systemic exposure to estimate the amount of drug absorbed by the lung. The Loo-Riegelman approach predicted lung absorption well in humans following DPI dosing. In rats, lung absorption was predicted well for IT dosing, but not DPI dosing, emphasizing caution in using systemic drug concentrations to predict lung concentrations in rats receiving a DPI dose.