SummaryWe have performed the fetal CO2response test on eight mature lambsin uteroand have found that theophylline is a respiratory stimulant over a wide range of PaO2and pHa. Theophylline produces significant increase in slope of P100, Pmax, and VEq response curves and significant increase in P100, Pmax, f, and VEq responses at PaCO2, 65 torr. It also produces significant lowering of the naturally high fetal absolute threshold to CO2,i.e., PaCO2at which breathing starts during the CO2test. “Offset” threshold,i.e., PaCO2when breathing stops after the test, is the same with and without theophylline and equal to absolute threshold with theophylline. Our studies indicate that: (1) theophylline lowers fetal threshold and increases sensitivity to CO2; (2) increased sensitivity is expressed mainly by heightened Pmax(i.e., the equivalent of tidal volume) with some contribution of f particularly at high PaCO2; (3) decreased CO2threshold is best assessed by determination of absolute threshold rather than the conventional x‐axis intercept method; (4) the low offset threshold is consistent with our understanding that arousal is a requisite for generation and maintenance of fetal breathing; (5) theophylline is as effective a respiratory stimulant during fetal acidemia and hypoxemia as it is under normal conditions; and (6) a number of serious reservations must be held regarding use of theophylline during low pHa, low PaO2states.SpeculationTheophylline, which is shown to be an effective respiratory stimulant in the ovine fetus, activates central respiratory units by a process of recruitment analogous to that of other inputs,e.g., somatosensory and chemoreceptor afferents. Changes in the state of respiratory center arousal, including its return to natural quiescence with apnea when inputs are withdrawn, can be assessed by the fetal CO2test and bear on the phenomena of onset of breathing at birth, neonatal apnea, and sudden infant death.