We examined ventilation and metabolism in four rat strains with variation in traits for body weight and/or blood pressure regulation. Sprague-Dawley [SD; 8 males (M), 8 females (F)], Brown Norway (BN; 10 M, 11 F), and Zucker (Z; 11 M, 12 F) rats were compared with Koletsky (K; 11 M, 11 F) rats. With the use of noninvasive plethysmography, frequency, tidal volume, minute ventilation (VE), O2 consumption, and CO2 production were derived at rest during normoxia (room air) and during the 5th minute of exposure to each of the following: hyperoxia (100% O2), hypoxia (10% O2-balance N2), and hypercapnia (7% CO2-balance O2). Statistical methods probed for strain and sex effects, with covariant analysis by body weight, length, and body mass. During resting breathing, strain effects were found with respect to both frequency (BN, Z > K, SD) and tidal volume (SD > BN, Z) but not to VE. Sex influenced frequency (F > M) alone. Z rats had higher values for O2 consumption, CO2 production, and respiratory quotient than the other three strains, with no independent effect by sex. During hyperoxia, frequency was greater in BN and Z than in SD or K rats; SD rats had a larger tidal volume than BN or Z rats; Z rats had a greater VE than K rats; and M had a larger tidal volume than F. Strain differences persisted during hypercapnia, with Z rats exhibiting the highest frequency and VE values. During hypoxic exposure, strain effects were found to influence VE (SD > K, Z), frequency (BN > K), and tidal volume (SD > BN, K, Z). Body mass was only a modest predictor of VE during normoxia, of both VE and tidal volume with hypoxia, hypercapnia, or hyperoxia, and of frequency during hypercapnia. We conclude that strain of rats, more than their body mass or sex, has major and different influences on metabolism, the pattern and level of ventilation during air breathing, and ventilation during acute exposure to hypercapnia or hypoxia.