Both short-term and life-long high altitude exposure challenge the cardiovascular system to meet the metabolic demand for oxygen (O2) in a hypoxic environment. As the demand for O2 delivery increases during exercise, the circulatory component of oxygen transport is placed under additional stress. Acute adaptation and chronic remodelling of cardiac structure and function may occur to facilitate O2 delivery in lowlanders during sojourn to high altitude and permanent highland residents. However, our understanding of cardiac adaptation in highlanders remains limited. The Sherpa, one of the most successful high altitude populations, are considered to be of Tibetan lineage and have resided at high altitude for over 25,000 years. Previous research suggests Sherpa are able to achieve higher maximal heart rates than acclimatised lowlanders and report a lower severity of hypoxic pulmonary vasoconstriction compared to other ethnic groups native to high altitude. Despite the potential for lower pulmonary pressures, neither the interaction of right ventricular (RV) afterload with cardiac structure and function, nor the relationship between RV function and left ventricular (LV) filling have been assessed. Ventricular form and function are intrinsically linked through the unique arrangement of myofibres that facilitate efficient ejection, minimize myofibre stress during contraction and aid diastolic recoil. The myocardial mechanics (twist, rotation and strain) that underpin ventricular function reflect this relationship and are known to acutely change and chronically remodel in response to altered physiological demand, as seen with hypoxia. Therefore, examination of myocardial mechanics allows detailed insight into cardiac adaptation in high altitude populations. Data from recent studies examining cardiac structure, function and mechanics in adolescent and adult Sherpa at high altitude and lowlanders before and after ascent to 5050 m will be presented. Collectively, our findings indicate chronic structural ventricular adaptation, with adult Sherpa having smaller absolute and relative ventricular size. In line with structural remodelling, cardiac mechanics also differ in Sherpa when compared to lowlanders at high altitude. These changes may reflect a functional cardiac adaptation that affords Sherpa the same mechanical reserve seen in lowlanders at sea level but not when they ascend to high altitude.