Physical inactivity and poor cardiorespiratory fitness (CRF) are strongly associated with type 2 diabetes (DM2) and all-cause and cardiovascular morbidity and mortality. Incorporating physical activity promotion in the management of DM2 has been a pivotal approach modulating the underlying pathophysiology of DM2 of increased insulin resistance, endothelial dysfunction, and abnormal mitochondrial function. Although CRF is considered a modifiable risk factor, certain immutable aspects such as age, race, and gender impact CRF status and is the focus of this review. Results show that diabetes has often been considered a disease of premature aging manifested by early onset of macro and microvascular deterioration with underlying negative impact on CRF and influencing next generation. Certain races such as Native Americans and African Americans show reduced baseline CRF and decreased gain in CRF in randomized trials. Moreover, multiple biological gender differences translate to lower baseline CRF and muted responsivity to exercise in women with increased morbidity and mortality. Although factors such as age, race, and sex may not have major impacts on CRF their influence should be considered with the aim of optimizing precision medicine.