Nowadays, interconnection wide electric transmission system has been envisioned to facilitate the growth of renewable energy, enhance reliability, improve system operating efficiency and reduce greenhouse gas emissions. In this thesis, we articulate an explicit planning framework for high-capacity, inter-regional transmission system design. The study framework begins with generation scenario design, followed by an innovative transmission candidate selection algorithm derived from graph theory applications. Then, a new modeling approach has been introduced to efficiently model the transmission network expansion optimization problem at the interconnection wide level. Global uncertainties have been addressed as well to design a transmission overlay which is robust to different future scenarios. Last, steady state operating benefits, in terms of total cost and CO2 emissions, are evaluated by a series of comparison studies between systems with and without designed overlays. The complete study process has been applied to an aggregated U.S. power system study case to design, optimize and evaluate transmission overlays for multiple future generation scenarios. Associated simulation results suggest that a national transmission overlay provides economic and environmental benefits.