Design of high temperature PEM (HTPEM) fuel cell systems requires special consideration of the elevated temperatures, and proper heat integration. Due to the increased tolerance to impurities, such as CO, in the anode hydrogen fuel flow these systems have a high degree of flexibility when it comes to choice of fuel. The shift towards higher temperatures is not without challenges, the materials (membranes, catalysts, stack and system components) are further stressed while also less mature, system startup time is longer and performance is lower than Nafion-based systems. However, HTPEM fuel cell systems have the potential of obtaining comparable efficiencies with other fuel cell technologies and in some cases provide more advantageous solutions due to the ease of cooling, reduced requirements for fuel quality and the possibility of using more readily available fuels that require smaller investments in infrastructure [1–4]. The introduction of fuel reformers also introduce additional complexity to a fuel cell system, and require in turn proper control strategies in order to obtain reliable and efficient system performance. This chapter presents some of the challenges and strategies involved with HTPEM fuel cell system design, some of the considerations to make, and examples of different relevant control strategies and their potentials for use in real operating systems. ; Various system topologies are available when it comes to designing high temperature PEM fuel cell systems. Very simple system designs are possible using pure hydrogen, and more complex system designs present themselves when alternative fuels are desired, using reformer systems. The use of reformed fuels utilizes one of the main advantages of the high temperature PEM fuel cell: robustness to fuel quality and impurities. In order for such systems to provide efficient, robust, and reliable energy, proper control strategies are needed. The complexity and nonlinearity of many of the components in such systems allow the development of both simple linear and also advanced fuzzy logic and neural network controllers able to adapt system performance to the ever changing conditions which the systems operate in over their entire lifetime.