Legislative challenges, changing customer needs and the opportunities opened-up by electrification are the major driving forces in today’s automotive industry. Fuel cell vehicles offer the potential for CO2 emission free mobility, especially attractive for heavy duty long-haul range application. The development of key components of fuel cell powered vehicles, namely the fuel cell stack itself as well as the related hydrogen/air supply and thermal management sub-systems, goes hand in hand with various challenges regarding performance, lifetime and safety. The proper layout and sizing of the stack and the related fuel and air supply system components, as well as the suitable dimensioning of the cooling system, are decisive for the overall system efficiency and achievable lifetime. Finally, the different components and sub-systems need to be integrated into the overall powertrain and vehicle configuration together with the related control functions to ensure proper operation under all driving scenarios and ambient conditions. In the above context, system simulation enables to support the development teams in the different phases of the development process, from concept layout, to detailed component and sub-system development to virtual integration and calibration. The current work presents such a versatile multi-physics simulation methodology and provides insights into the modelling fundamentals regarding the various components and subsystems adopted. To confirm the validity of the underlying modelling, comparisons of simulation results with corresponding experimental data are presented for selected fuel cell system components and operating conditions. The applicability of the overall simulation framework to support the development and optimization of fuel cell systems is demonstrated for selected use-cases.