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Summary form only for tutorial. The design of complex integrated systems faces a growing number of challenges from two frontiers. First, the increasing unpredictability of the progressing semiconductor manufacturing process requires new analysis and optimization approaches that utilize comprehensive modeling of process uncertainties for driving a novel, variation-aware design optimization flow. Second, the increasing system complexity demands new specification methods at higher levels of abstraction that can support efficient architectural exploration, functional verification, and implementation flows. Both challenges require a tight integration of the overall design tool flow resulting in a departure from traditional sequencing of point-tools. In this presentation we discuss a number of these problems in detail and outline possible approaches to their solutions. We further address their impact on algorithmic design and tool integration and discuss new opportunities for academic researchers to help overcome these challenges.