Space mapping arose from the need to implement fast and accurate design optimization of microwave structures using full-wave EM simulators. Space mapping optimization later proved effective in disciplines well beyond RF and microwave engineering. The underlying coarse and fine models of the optimized structures have been implemented using a variety of EDA tools. More recently, measurement-based physical platforms have also been employed as “fine models.” Most space-mapping-based optimization cases have been demonstrated at the device-, component-, or circuit-level. However, the application of space mapping to high-fidelity system-level design optimization is just emerging. Optimizing highly accurate systems based on physical measurements is particularly challenging, since they are typically subject to statistical fluctuations and varying operating or environmental conditions. Here, we illustrate emerging demonstrations of space mapping system-level measurement-based design optimization in the area of signal integrity for high-speed computer platforms. Other measurement-based space mapping cases are also considered. Unresolved challenges are highlighted and potential general solutions are ventured.ITESO, A.C.