The natural course of chronic obstructive pulmonary disease (COPD) is complicated by the development of systemic consequences and co-morbidities. These may be major features in the clinical presentation of COPD, prompting increasing interest. Systemic consequences may be defined as non-pulmonary manifestations of COPD with an immediate cause-and-effect relationship, whereas co-morbidities are diseases associated with COPD. The major systemic consequences/co-morbidities now recognized are: deconditioning, exercise intolerance, skeletal muscle dysfunction, osteoporosis, metabolic impact, anxiety and depression, cardiovascular disease, and mortality. The mechanisms by which these develop are unclear. Probably many factors are involved. Two appear of paramount importance: systemic inflammation, which presents in some patients with stable disease and virtually all patients during exacerbations, and inactivity, which may be a key link to most COPD-related co-morbidities. Further studies are required to determine the role of inflammatory cells/mediators involved in systemic inflammatory processes in causing co-morbidities; the link between activity and co-morbidities; and how COPD therapy may affect activity. Both key mechanisms appear to be influenced significantly by COPD exacerbations. Importantly, although the prevalence of systemic consequences increases with increasing severity of airflow obstruction, both systemic consequences and co-morbidities are already present in the Global Initiative for Chronic Obstructive Lung Disease Stage II. This supports the concept of early intervention in chronic obstructive pulmonary disease. Although at present early intervention studies in COPD are lacking, circumstantial evidence suggests that current treatments may influence events leading to the systemic consequences and co-morbidities, and thus may affect the clinical manifestations of the disease.