The mechanisms of chronic ventilatory failure in chronic obstructive pulmonary disease are complex. This paper analyses the diverse available information: mechanical factors and gas-exchange, fighter vs. non-fighter, the ventilatory pattern theory and the fatigue threshold theory. Finally we comment on the evidence supporting the new concept that hypercapnia may develop to avoid or prevent fatigue. Indeed, it is very likely that chronic CO2 retention in COPD may develop by mechanical disadvantages of the inspiratory muscles rather than impairment of ventilation-perfusion ratios. This opens a fascinating new research line on the neuromechanical control of breathing. When the respiratory effort is approaching the fatigue level, the respiratory muscles may elicit a negative feedback reflex, the muscle activity is depressed and hypercapnia develops. If this is so, chronic hypercapnia may be an index of imminent fatigue if increases in ventilation or work of breathing are required. Under this condition some degree of central diaphragm fatigue may help to protect the muscle from severe or limiting peripheral fatigue or even muscle injury. Finally, we comment on some therapeutic approaches such as ventilatory stimulants, training, rest and, specially, oxygen administration and the mechanisms involved in the PCO2 increases.