Development challenges in the automotive industry are constantly increasing due to the high number of vehicle variants, the growing complexity of powertrains, and future legal requirements. In order to reduce development times while maintaining a high level of product quality and financial feasibility, the application of new model-based methods for virtual powertrain calibration is a particularly suitable approach. In this context, TME and FEV combine advanced thermal management models with electronic control unit (ECU) models for model-in-the-loop applications. This paper presents a development process for ECU and on-board diagnostics (OBD) functions of thermal management systems in hybrid electric vehicles. Thanks to the highly accurate 1D/3D-models, optimal control strategies for electrically actuated components can be developed in early development phases. Virtual sensors for local temperatures are developed for the ECU software to enable a cost-effective use of dedicated control functions. Furthermore, an application for OBD cooling system leakage detection is shown. Finally, the transferability of the methodology to a battery cooling system is demonstrated.