The impact of genetic variation on cardiovascular responses to hypoxia and hypercapnia is not well understood. Therefore, we determined the acute changes in systemic arterial blood pressure (P(SA)) and heart rate (HR) in seven strains of commonly used inbred mice exposed to acute periods of hypoxia (10% O(2)), hypercapnia (5% CO(2)), and hypoxia/hypercapnia (10% O(2) + 5% CO(2)) during wakefulness. Hypercapnia induced an essentially homogeneous response across strains, with P(SA) maintained at or slightly above baseline and with HR exhibiting a typical baroreceptor-mediated bradycardia. In contrast, exposure to hypoxia elicited a marked heterogeneity in cardiovascular responses between strains. The change in P(SA) during hypoxia ranged from maintenance of normotension in the FVB/J strain to profound hypotension of approximately 30 mmHg in the DBA/2J strain. HR responses were highly variable between strains during hypoxia, and with the exception of the DBA/2J strain that exhibited significant bradyarrhythmias and consequent hypotension, the HR responses were unrelated to changes in P(SA). The P(SA) response to combined hypoxia/hypercapnia represented a balance of the hypertension of hypercapnia and the hypotension of hypoxia in six of the seven strains. In the FVB/J strain, combined hypoxia/hypercapnia produced a hypertensive response that was greater than that of hypercapnia alone. These results suggest that genetic background affects the cardiovascular response to hypoxia, but not hypercapnia.