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As the semiconductor technology roadmap further extends, the development of next generation silicon systems becomes critically challenged. On the one hand, design and manufacturing closures become much more difficult due to the widening gap between the increasing integration density and the limited manufacturing capability. As a result, manufacturability issues become more and more critically challenged in the design of reliable silicon systems. On the other hand, the continuous scaling of feature size imposes critical issues on traditional interconnect materials (Cu/Low-K dielectrics) due to power, delay and bandwidth concerns. As a result, multiple classes of new materials are under research and development for future generation technologies. In this dissertation, we investigate several critical Computer-Aided Design (CAD) challenges under advanced nanolithography and nanophotonics technologies. In addressing these challenges, we propose systematic CAD methodologies and optimization techniques to assist the design of high-yield and high-performance integrated circuits (IC) with low power consumption. In Very Large Scale Integration (VLSI) CAD for nanolithography, we study the manufacturing variability under resolution enhancement techniques (RETs) and explore two important topics: (1) fast and high fidelity lithography hotspot detection; (2) generic and efficient manufacturability aware physical design. For the first topic, we propose a number of CAD optimization and integration techniques to achieve the following goals in detecting lithography hotspots: (a) high hotspot detection accuracy; (b) low false-positive rate (hotspot false-alarms); (c) good capability to trade-off between detection accuracy and false-alarms; (d) fast CPU run-time; and (e) excellent layout coverage and computation scalability as design gets more complex. For the second topic, we explore the routing stage by incorporating post-RET manufacturability models into the mathematical formulation of a detailed router to achieve: (a) significantly reduced lithography-unfriendly patterns; (b) small CPU run-time overhead; and (c) formulation generality and compatibility to all types of RETs and evoling manufacturing conditions. In VLSI CAD for nanophotonics, we focus on three topics: (1) characterization and evaluation of standard on-chip nanophotonics devices; (2) low power planar routing for on-chip opto-electrically interconnected systems; (3) power-efficient and thermal-reliable design of nanophotonics Wavelength Division Multiplexing for ultra-high bandwidth on-chip communication. With simulations and experiments, we demonstrate the critical role and effectiveness of Computer-Aided Design techniques as the semiconductor industry marches forward in the deeper sub-micron (45nm and below) domain. / text