With remarkable advances in computing power, computer experiments continue to expand the boundaries and drive down the cost of various scientific discoveries. New challenges keep arising from designing, analyzing, modeling, calibrating, optimizing, and predicting in computer experiments. This dissertation consists of six chapters, exploring statistical methodologies in sequential learning, model calibration, and uncertainty quantification for heteroskedastic computer experiments and large-scale computer experiments. For heteroskedastic computer experiments, an optimal lookahead based sequential learning strategy is presented, balancing replication and exploration to facilitate separating signal from input-dependent noise. Motivated by challenges in both large data size and model fidelity arising from ever larger modern computer experiments, highly accurate and computationally efficient divide-and-conquer calibration methods based on on-site experimental design and surrogate modeling for large-scale computer models are developed in this dissertation. The proposed methodology is applied to calibrate a real computer experiment from the gas and oil industry. This on-site surrogate calibration method is further extended to multiple output calibration problems.