Power density, efficiency, cost, and reliability are the major challenges when designing a power electronic system. Latest advancements in power semiconductor devices (e.g., silicon carbide devices) and topological innovations have vital contributions to power density and efficiency. Nevertheless, dedicated heat sink systems for thermal management are required to dissipate the power losses in power electronic systems; otherwise, the power devices will be heated up and eventually fail to operate. In addition, in many mission critical applications (e.g., marine systems), the operating condition (i.e., mission profiles) is usually harsh, where the input power can change quickly and randomly, resulting in considerable temperature swings in the power electronics. This may induce failures to the power electronic systems. If remain untreated (i.e., ill-designed system without considering reliability), the cost for maintenance will increase, thus affecting the reputation for the manufacturers and, more important, the cost of energy in renewables. Hence, it calls for highly reliable power electronic systems, where the reliability together with various common design parameters should be taken into account in the design phase. Clearly, it is a prerequisite to know the main life-limiting factors in order to predict the lifetime. Then, the design for reliability (DfR) can be performed. In this chapter, the technological challenges in the DfR of power electronic systems are addressed and how the power electronics are loaded considering mission profiles is demonstrated. Further, the DfR approach is systematically exemplified in grid-connected photovoltaic power electronic systems.