Two-dimensional (2D) semiconductors offer good mobilities and high drive currents in atomically thin layers, thereby enabling excellent gate control in ultra-short channel devices. However, numerous challenges must be overcome for 2D materials to be used in commercial applications, including the formation of contacts and the identification of scalable and reliable gate insulators. To enable the transition from prototype devices to integrated circuits at an industrial scale, physical predictive modeling tools are required for 2D transistors. Here we show, based on three different device examples, how TCAD and compact models can be used to describe the performance and reliability of 2D transistors. We investigate two device types based on MoS2 using SiO2 as the gate insulator and one based on the novel tertiary layered zipper material Bi2O2Se and its native oxide Bi2SeO5. We use our models to benchmark the device performance and offer valuable insights into transistor operation, thereby revealing promising approaches for performance improvements.