Complex systems appear when interaction among system components creates emergent behavior that is difficult to be predicted from component properties. The growth of Internet of Things (IoT) and embedded technology has increased complexity across several sectors (e.g., automotive, aerospace, agriculture, city infrastructures, home technologies, healthcare) where the paradigm of cyber-physical systems (CPSs) has become a standard. While CPS enables unprecedented capabilities, it raises new challenges in system design, certification, control, and verification. When optimizing system performance computationally expensive simulation tools are often required, and search algorithms that sequentially interrogate a simulator to learn promising solutions are in great demand. This class of algorithms are black-box optimization techniques. However, the generality that makes black-box optimization desirable also causes computational efficiency difficulties when applied real problems. This thesis focuses on Bayesian optimization, a prominent black-box optimization family, and proposes new principles, translated in implementable algorithms, to scale Bayesian optimization to highly expensive, large scale problems. Four problem contexts are studied and approaches are proposed for practically applying Bayesian optimization concepts, namely: (1) increasing sample efficiency of a highly expensive simulator in the presence of other sources of information, where multi-fidelity optimization is used to leverage complementary information sources; (2) accelerating global optimization in the presence of local searches by avoiding over-exploitation with adaptive restart behavior; (3) scaling optimization to high dimensional input spaces by integrating Game theoretic mechanisms with traditional techniques; (4) accelerating optimization by embedding function structure when the reward function is a minimum of several functions. In the first context this thesis produces two multi-fidelity algorithms, a sample driven and model driven approach, and is implemented to optimize a serial production line; in the second context the Stochastic Optimization with Adaptive Restart (SOAR) framework is produced and analyzed with multiple applications to CPS falsification problems; in the third context the Bayesian optimization with sample fictitious play (BOFiP) algorithm is developed with an implementation in high-dimensional neural network training; in the last problem context the minimum surrogate optimization (MSO) framework is produced and combined with both Bayesian optimization and the SOAR framework with applications in simultaneous falsification of multiple CPS requirements.