Current concepts of cystic fibrosis (CF) pathophysiology link ion transport abnormalities to reduced airway surface liquid (ASL) hydration and impaired mucus clearance. It is likely that correction of the defects that cause ASL dehydration will prevent degradation of mucus clearance, thereby preventing the initiation and/or progression of CF lung disease. A number of novel therapeutic agents aimed at the earliest steps in disease pathogenesis are now under development for the treatment of CF lung disease. Consequently, there is a tremendous need to develop methods that directly assess the effects of these agents on the underlying pathophysiologic process in the target organ. The measurement of mucociliary clearance (MCC) is a highly biologically relevant outcome, but one that is in need of further development. Here, we describe important methodologic aspects of MCC measurement and issues that have limited its use as an outcome measure in the past. Furthermore, we outline the steps that are being carried out now, and will be carried out in the future, to improve the performance of these studies in clinical trials. A systematic approach to optimizing and standardizing the measurement of MCC should greatly advance our ability to assess novel therapies at a relatively early stage of drug development. The resulting data may then be used to select those candidates that should be rapidly advanced into larger clinical trials.