To evaluate the effectiveness, constraints, and costs of the cross-layer reliability and variability mitigation framework, a holistic simulation flow needs to be developed, in which the simulations of each layer are incorporated. Here, we developed a workload-dependent simulation framework for each level of mitigation. Combining individual simulations, we can perform cross-layer simulations to reveal the interdependency among layers, as well as the figures of merits in the reliability of the holistic system. The simulation framework can be further used for co-simulation and co-optimization of system parameters across all layers for maximizing reliability while minimizing cost. This chapter is structured as follows: The overall simulation framework of the cross-layer reliability and variability mitigation framework is introduced in Sect. 8.1. The following sections show the experiments on the system reliability with different layers of the framework. In Sect. 8.2, we show a workload-dependent error simulation flow to evaluate the effect of the circuit-layer mitigation. Then, Sect. 8.3 demonstrates a cross-layer co-simulation combining the register layer and the processor layer to reveal their interdependencies. Finally, the effect of optimal checkpointing on the system is analyzed in Sect. 8.4, showing how changing system parameters can improve the reliability of the system.