Biomarker development in chronic obstructive pulmonary disease (COPD) is a nascent field, in part because of the complexity underlying COPD pathogenesis. The objective of this review is to provide examples of how biomarkers may be effectively applied in clinical trials of COPD by limiting their use to specific contexts and using them to answer well delineated questions. Types of novel outcomes or "biomarkers" that may be useful in clinical trials in COPD include analyses performed on bronchoscopically obtained samples, sputum, exhaled gases, blood, and urine and "ex vivo" assays performed using biological samples obtained from trial participants. These novel biological outcomes are rarely useful as primary end points in phase III clinical trials in COPD, because they are not typically recognized by the U.S. Food and Drug Administration or other regulatory agencies. More commonly, the applications of these outcomes include "proof-of-concept" decisions, demonstration that the intervention had the intended pharmacologic or biological effect, identification of patient subgroups that benefit most, and safety monitoring. Examples given in this review include outcomes used in a phase IIA study of an inhaled small molecule inhibitor of epidermal growth factor receptor. Large observational studies of COPD, including the ECLIPSE, COPDGene, and SPIROMICS studies will further inform our use of biomarkers in COPD clinical trials. To encourage the application of novel biomarkers in clinical trials, the Food and Drug Administration has developed a new process for biomarker "qualification." This process has been designed to be more efficient and to promote consensus building and sharing of preclinical data.