The unabated silicon technology scaling makes design and manufacturing increasingly harder in nanometer VLSI. Emerging technologies on the horizon require strong design automation to handle the large complexity of future systems. This dissertation studies eight related research topics in design and manufacturing closure in nanometer VLSI as well as design optimization for emerging technologies from physical synthesis perspective. In physical synthesis for design closure, we study three research topics, which are key challenges in nanometer VLSI designs: (a) We propose a highly efficient floorplanning algorithm to minimize substrate noise for mixed-signal system-on-a-chip designs. (b) We propose a clock tree synthesis algorithm to reduce clock skew under thermal variation. (c) We develop a global router, BoxRouter to enhance routability which is one of the classic but still critical challenges in modern VLSI. In physical synthesis for manufacturing closure, we propose the first systematic manufacturability aware routing framework to address three key manufacturing challenges: (a) We develop a predictive chemical-mechanical polishing model to guide global routing in order to reduce surface topography variation. (b) We formulate a random defect minimize problem in track routing, and develop a highly efficient algorithm. (b) We propose a lithography enhancement technique during detailed routing based on statistical and macro-level Post-OPC printability prediction. Regarding design optimization of emerging technologies, we focus on two topics, one in double patterning technology for future VLSI fabrication and the other in microfluidics for biochips: (a) We claim double patterning should be considered during physical synthesis, and propose an effective double patterning technology aware detailed routing algorithm. (b) We propose a droplet routing algorithm to improve routability in digital microfluidic biochip design. / text