COPD is a major cause of death and disability worldwide. Treatment of COPD improves lung function but is unlikely to slow the steady downhill course of the disease or reduce mortality. In COPD, numerous abnormalities can be found outside the lung. These include systemic inflammation, cachexia, and skeletal muscle dysfunction. Thus, COPD has been called a systemic disease. Convincing data demonstrate that COPD causes neurohumoral activation. By precedents derived from chronic heart failure and other diseases characterized by neurohumoral activation, we propose that the negative consequences of neurohumoral activation, namely inflammation, cachexia, effects on ventilation, and skeletal muscle dysfunction, give rise to a self-perpetuating cycle that contributes to the pathogenesis of COPD, and which may involve respiratory muscle dysfunction as well as systemic inflammation. This concept may further help explain the increased cardiovascular morbidity and mortality in COPD patients. Currently, little is known about the effect of treatments directed at neurohumoral activation and COPD. As this aspect of COPD becomes better understood, new insights may direct novel therapeutic approaches.