Measurements of disease severity provide a guide for the physician to tailor therapies, for the patient and family to gauge progress, and are required for clinical trials. For many respiratory diseases, including cystic fibrosis, sensitive, noninvasive measurements are few, and some of those that are available are applicable only to certain subgroups of patients or lack sufficient sensitivity. We discuss currently available measurements in 4 groups: physiology, infection, inflammation, and radiology. For each group we highlight strengths and weaknesses, ask how we could improve upon these, and provide details of alternative methods.