This paper considers the optimization of thermal systems and processes, which are of interest in a wide range of practical applications, on the basis of mathematical and numerical modeling as well as experimental data. Many complexities, such as property variations, complicated regions, combined transport mechanisms, chemical reactions, and intricate boundary conditions, typically arise in these systems, making experimentation and numerical simulation quite challenging. Consequently, many studies have obtained detailed results on the processes without going further into system design. Also, many important systems have not been optimized for best performance or output. This paper focuses on the practical aspects of obtaining an optimum in thermal systems and processes. Of particular interest are validation of the model and linking the simulation with system performance, design, and optimization. Optimization is considered both for the operating conditions as well as for the hardware of the system. Starting with a feasible domain that leads to an acceptable design, different optimization strategies may be employed. Both deterministic conditions and those with uncertainty are of interest and are outlined. Of particular interest is multiobjective optimization, since most thermal systems involve several important objectives, such as heat transfer rate and pressure in electronic cooling systems and product quality and production rate in manufacturing systems. The optimization is often a constrained one due to limitations on materials, cost, and operating conditions that determine the acceptable domain. Nature is replete with interesting examples where constrained multiobjective optimization is employed by various living creatures for food, safety, mobility, and other aspects of survival. A study of such natural phenomena can also be used in technology as we seek an optimum. Such nature-inspired optimization is discussed. Overall, the focus is on realistic and practical approaches that may be adopted to optimize thermal systems and processes to minimize energy consumption, enhance productivity, reduce environmental impact, improve heat transfer and achieve other objectives.