While COPD affects far more than 200,000 people in the United States, COPD is not a disease in the narrow sense that tuberculosis is. COPD is defined on the basis of a single physiologic parameter, reduced expiratory airflow.5 In this regard, COPD is more like “fever.” Not so long ago, a great variety of diseases would have been classified as a fever, including tuberculosis, plague, Hodgkin disease, and familial Mediterranean fever, among a very large group of diseases, many of which are rare and now qualify as orphan conditions. Without doubt, fevers are more heterogeneous than COPD. Nevertheless, COPD is an extremely heterogeneous disorder. Current concepts suggest that it results from the complex interactions of many genetic factors, most of which remain undefined, that interact with many environmental factors, the most of important of which is cigarette smoking. This etiologic and mechanistic heterogeneity creates both opportunities and problems for the development of rational therapies. For example, inflammation likely plays a key role in the development of COPD. However, in COPD patients, there are several different inflammatory responses that vary qualitatively and quantitatively; it is likely that there are many pathways for their pathogenesis.6 Many mechanistically based interventions, therefore, are reasonable. Unfortunately, it seems plausible that most will be dramatically effective for a subset of COPD patients, but useless (or worse) for others. The classification of COPD, or at least the determination of definable subsets of COPD patients who share common mechanistic pathways that would be appropriate for a specific intervention as an orphan disease, is appropriate to address this problem.