Reliability is an important issue for safety operation of circuits in critical applications such as military, aerospace, energy, and biomedical engineering. With the rise of failure rate in nanometer CMOS technologies, the need for reliability has become more pressing in the recent years. General design methodologies considers classical criteria such as area, speed, and power consumption. Design for reliability methodologies are often implemented using post-synthesis reliability analysis and simulation tools. In this chapter, an automated system design for reliability is pro- posed. The innovative methodology is capable of identifying the system-level optimum while accounting for considering circuit’s reliability in early design stages. The proposed methodology is illustrated by the selection of an optimal design strategy considering reliability as a design criterion. An RF front-end design is presented. Experimental results are drawn from five different design strategies, which consider a classical and four reliability-oriented designs. From design for reliability strategies, results indicate that Higher Energy strategy is the most suitable. This strategy takes variability and aging into consideration, and achieves convergence in 3.83 s. A system-level reliability modelling has been applied to guarantee the methodology convergence. If there is no solution for performance and reliability requirements, this methodology also identifies hard constraints using a sensitivity analysis. To the best of our knowledge, this is the first work including reliability constraints in an automated system-level design.