Rafferty, G. F., and W. N. Gardner. Control of the respiratory cycle in conscious humans. J. Appl. Physiol. 81(4): 1744-1753, 1996.We studied in conscious humans the relative strength of mechanisms controlling timing and drive components of the respiratory cycle around their resting set points. A system of auditory feedback with end-tidal PCO₂ held constant in mild hyperoxia via an open circuit was used to induce subjects independently to change inspiratory time (TI) and tidal volume (VT_I) over a wide range above and below the resting values for every breath for up to 1 h. Four protocols were studied in various levels of hypercapnia (1-5% inspired CO₂). We found that TI (and expiratory time) could be changed over a wide range (1.17-2.86 s, P < 0.01 for TI) and VT_I increased by 500 ml (P < 0.01) without difficulty. However, in no protocol was it possible to decrease VT_I below the free-breathing resting value in response to reduction of auditory feedback thresholds by up to 600 ml. This applied at all levels of chemical drive studied, with resting VT_I values varying from 1.06 to 1.74 liters. When reduction in VT_I was forced by the more "programmed" procedure of isocapnic panting, end-expiratory volume was sacrificed to ensure that peak tidal volume reached a fixed absolute lung volume. These results suggest that the imperative for control of resting breathing is to prevent reduction of VT_I below the level dictated by the prevailing chemical drive, presumably to sustain metabolic requirements of the body, whereas respiratory timing is weakly controlled consistent with the needs for speech and other nonmetabolic functions of breathing.