Exceptional loads on buildings and structures may have different causes, including high-strain dynamic effects due to natural hazards, man-made attacks, and accidents, as well as extreme operational conditions (severe temperature variations, humidity, etc.). All these aspects can be critical for specific structural typologies and/or materials that are particularly sensitive to unfavorable external conditions. In this regard, dedicated and refined methods are required for their design, analysis, and maintenance under the expected lifetime. However, major challenges are usually related to the structural typology and materials object of study, with respect to the key features of the imposed design loads. Further issues can be derived from the need for the mitigation of adverse effects or retrofit of existing structures, as well as from the optimal and safe design of innovative materials/systems. Finally, in some cases, no appropriate design recommendations are currently available in support of practitioners, and thus experimental investigations (both on-site or on laboratory prototypes) can have a key role within the overall structural design and assessment process. This Special Issue presents 19 original research studies and two review papers dealing with the structural performance of buildings and structures under exceptional loads, and can represent a useful answer to the above-mentioned problems.