There has been increasing interest in developing novel pulmonary biomarkers to assist in drug and device development in the setting of patients with chronic obstructive pulmonary disease and diffuse parenchymal lung disease. In this review we discuss which computed tomography (CT)-based biomarkers are currently being implemented and the challenges inherent in their development, validation, and implementation in multicenter trials. CT scans provide valuable information about lung structure and function but face challenges with respect to standardization across multiple sites and time points; in addition, the concern around radiation has to be considered. There is relatively little information about how any of these biomarkers relate to other clinical outcomes such as progression of disease, severity of disease, clinical subtypes, or response to therapy. Additional information is also needed about the variability in these measurements. In the future, CT biomarkers may be useful in predicting disease progression, in indicating disease instability, and in predicting response to current and novel therapies, many of which are now under development.