This chapter examines the optimization of grillage systems and frame structures, which represent more complex assemblies compared to individual members or trusses. Analytical formulations and computational approaches are discussed, with attention to challenges posed by high degrees of redundancy and multiple load conditions. The chapter emphasizes the importance of modeling accuracy, especially in capturing stiffness distribution and interaction between components. Applications include building frames, bridge decks, and structural systems where geometry and loading are highly variable. By presenting optimization techniques for these interconnected systems, the chapter illustrates how mathematical strategies extend beyond individual elements to full structural assemblies, providing engineers with tools for achieving efficient, safe, and sustainable designs in real-world practice.