When the ventilatory muscles are unable to develop the required force as it occurs during fatigue, hypercapnic respiratory failure ensues. We present evidence that when the respiratory muscles work in a fatiguing load domain the central controllers respond at an early stage with tachypnea, while when the muscles fail bradypnea ensues which is followed by apnea. Although bradypnea and apnea in addition to muscle inability to develop force may reduce alveolar ventilation by virtue of reducing the total minute ventilation, tachypnea may also be followed by hypercapnia at constant total minute ventilation by virtue of a reduction in tidal volume (VT). Such a strategy will increase the ratio of dead space (VD) to tidal volume (VD/VT) and PCO2 will rise. It is argued that this mechanism could satisfactorily explain the high levels of CO2 in patients with chronic obstructive lung disease, as well as the CO2 retention at an early stage in acute cases of fatigue during, for example, the weaning period of a patient from the respirator. Bradypnea and apnea contribute to CO2 retention at a later stage, when the muscles are exhausted and total ventilation decreases. This sequence in frequency of breathing is explained as an advantageous strategy adopted for the respiratory muscles, because it allows the muscles to operate at an optimal length. It is also hypothesized that muscle afferents, probably via the small fibers III and IV and/or Golgi and tendon organs, are responsible for this interaction of CNS and respiratory muscles.