In this chapter, we further discuss how to extend the state-of-the-art mitigation approaches to tackling device- and circuit-level performance variability. To achieve this, multiple mitigation approaches need to be integrated to form a cross-layer mitigation framework which can deal with different kinds of variability and errors. In the framework, each layer tackles a type of variability or errors produced from the lower layers and generates variability or errors which should be tackled by the upper layers. The framework can not only ensure timing guarantees but also ensure functional correctness at the same time. Here, the principles and theoretical basis of the framework are elaborated. Then, Chap. 8 will discuss the experiments on testing the capability, cost, and limitations of this mitigation framework. This chapter is structured as follows: Sect. 7.1 describes the motivation and overview of the cross-layer framework, which consists of three layers. Then, we further elaborate on the details of each layer, respectively, from the bottom to the top in Sects. 7.2–7.4. The first layer, mitigation of device-level variability (process, voltage, and short-term aging effects), is described in Sect. 7.2. Then, the second layer, mitigation of errors, is described in Sect. 7.3. After that, we describe the last layer, mitigation of performance variability, in Sect. 7.4. Then, Sect. 7.5 describes how the overall reliability of the system can be evaluated with the cross-layer framework. Finally, we discuss some extensive questions about the framework in Sect. 7.6, including the comparisons with other cross-layer reliability frameworks and the applicability to other architectures and technologies.