Decarbonization and sustainability mandates pose serious uncertainties to the future of Internal Combustion Engines (ICEs). Achieving levels of competitive efficiency and power density with zero-emissions, necessitates cooperation with specialized organizations that can provide holistic system solutions.  Key elements of the engine system like ignition, injector, and combustion chamber components cannot be piecemealed together but must be properly integrated to realize the synergy needed to meet or exceed performance targets. Validated 1D system simulation and 3D combustion CFD models are tools used to create the requirements and specifications for a holistic system solution.  Specifically, the prechamber must feature a compound vortex flow to be able to operate with ultra-lean lambdas while assuring high combustion stability.  Also, the ignition system must be able to adapt the spark power during discharge based on the location of the spark occurrence.  This ensures proper ignition while preventing the formation of hot spots, leading to combustion instabilities.  In a similar fashion, the injector must enable effective mixing to achieve highly homogenous mixture needed to prevent the formation of rich pockets resulting in combustion anomalies caused by lubrication oil preignition (LOP). The key attributes of the prechamber, the ignition, and the injector enabling the high-performance of heavy-duty hydrogen engines are showcased in this paper. The results from detailed CFD simulations showing the path to highly effective mixing enabled by the advanced H2 injector during steady state, as well as during transient, are thoroughly described. Moreover, the implementation of a holistic system solution in a heavy-duty hydrogen engine and the test results in terms of engine efficiency, power density, transient response, and emissions are discussed in detail vis-à-vis the potential to achieve diesel-like performance with zero-emissions.