Turbochargers are a key technology for reducing the fuel consumption and CO2 emissions of heavy-duty internal combustion engines by enabling greater power density, which is essential for engine downsizing and downspeeding. This in turn raises turbine expansion ratio levels and drives the shift to air systems with multiple stages, which also implies the need for interconnecting ducting, all of which is subject to tight packaging constraints. This paper considers the challenges in the aerodynamic optimization of the exhaust side of a two-stage air system for a Caterpillar 4.4-litre heavy-duty diesel engine, focusing on the high pressure turbine wheel and interstage duct. Using the current production designs as a baseline, a genetic algorithm-based aerodynamic optimization process was carried out separately for the wheel and duct components in order to minimize the computational effort required to evaluate seven key operating points. While efficiency was a clear choice for the cost function for turbine wheel optimization, the most appropriate objective for interstage duct optimization was less certain, and so this paper also explores the resulting effect of optimizing the duct design for different objectives. Results of the optimization generated differing turbine wheel and interstage duct designs depending on the corresponding operating point, thus it was important to check the performance of these components at every other operating point, in order to determine the most appropriate designs to carry forward. Once the best compromise high pressure turbine wheel and interstage duct designs were chosen, prototypes of both were manufactured and then tested together against the baseline designs to validate the CFD predictions. The best performing high pressure turbine design, wheel A, was predicted to show an efficiency improvement of 2.15 percentage points, for on-design operation. Meanwhile, the optimized interstage duct contributed a 0.2 and 0.5 percentage-point efficiency increase for the high and low pressure turbines, respectively.