The aim of this study was to characterize the response to exercise training in several mouse strains and estimate the genetic contribution to phenotypic variation in the responses to exercise training. Male mice from three inbred strains [C57Bl/6J (BL6), FVB/NJ (FVB), and Balb/cJ (Balb/c)] and three hybrid F₁ strains [CB6F1/J (CB6 = female Balb/c × male BL6), B6F F₁ (female BL6 × male FVB), and FB6 F₁ (female FVB × male BL6)] completed an exercise performance test before and after a 4-wk treadmill running program. Distance was used as the primary estimate of endurance exercise performance. FVB mice showed the greatest response to training, with five- to sevenfold greater increases in distance run compared with BL6 and Balb/c strains. Specifically, BL6, FVB, and Balb/c strains increased distance by 33, 172, and 23%, respectively. A similar pattern of changes across strains was observed for run time (17, 87, and 11%) and work (99, 287, and 57%). As a group, F₁ hybrid mice derived from BL6 and FVB strains showed an intermediate response to training (61%). However, further analysis indicated that training responses in FB6 F₁ mice (80%) were ∼2.5-fold greater than responses in B6F F₁ mice (33%, P = 0.08). A similar pattern of changes between FB6 and B6F F₁ mice was observed for run time (44.5 and 17%) and work (141 and 59%). These data demonstrate that there are large strain-dependent differences in training responses among inbred mouse strains, suggesting that genetic background contributes significantly to adaptation to exercise. Furthermore, the contrasting responses in B6F and FB6 F₁ strains show that a maternal component strongly influences strain-dependent differences in training responses.