The influence of genetic factors on complex phenotypes is context dependent, posing a challenge to quantify the role of single gene variants on this process. Moreover, redundancy and reserve capacity among control systems prevents most physiological stimuli to destabilize these processes. To test whether small gene perturbation can disrupt this equilibrium under pathological conditions, mice harboring 1, 2 or 3 copies of the Ace gene were submitted to 3 and 6 weeks of pressure overload (PO). Direct systolic blood pressure (SBP), as an index of cardiac afterload, and left ventricle mass index (LVMI) were measured. LVMI under normotension was the same regardless of the Ace genotype but the slopes of the LVMI/SBP curves increased in the 3 vs. 1-copy group by about 50% upon 3 or 6- week PO. Angiotensin II AT1 receptor blocker treatment produced a significant pressure independent decrease in the LVMI/SBP ratio. Unlike the 1-copy group, PO resulted in a significant reduction in angiotensinogen and an increase in Ace mRNA expression accompanied by an increase in cardiac angiotensin II levels in the 3-copy group. Similarly, the human ACE D gene variant influenced cardiac mass, estimated by Sokolov-Lyon index, in a sample of 1507 individuals from an urban population only in individuals in the 4^th quartile of the blood pressure distribution. Collectively, these data provide direct evidence that Ace gene dosage per se does not influence cardiac mass but upon a pathological stimulus, such as elevation in blood pressure, it modulates cardiac mass in both mice and humans.