Mesoporous materials with various structures have attracted considerable attention due to their distinctive properties such as large pore sizes, high surface areas, tunable pore structures, and controllable framework compositions. Among them, spherical mesoporous materials (SMMs) are of great interest owing to the unique spherical shape, which show the closed packing nature and lowest surface energy. The open mesopores and short channels of SMMs not only increase the density of high accessible active sites but also facilitate the mass diffusion with short length. These characteristics are particularly useful for applications in catalysis, adsorption, energy storage and conversion, biomedicine, and so on. In addition, the creation of a spherical shape is conformable to the law of natural selection because objects in nature tend to minimize energy, while the sphere is one of the most perfect matter structures. Therefore, the design and synthesis of SMMs are very important from both fundamental and technological viewpoints. Compared to the simple single-level, SMMs with more complex multilevel structures inevitably bring unusual mechanical, electrical, and optical properties, which are highly desired for practical applications. For example, the construction of core-shell structured SMMs has inspired great attention as they can combine multiple components into one functional unit, exhibiting ameliorated or new physicochemical properties, which cannot be obtained from the isolated one. The presence of a hollow cavity in the yolk-shell structure allows sufficient exposure of the core while maintaining the protective ability of the shell, which is conducive to retaining the distance-dependent properties of the core. Multishelled hollow structures consisting of two or more mesoporous shells are expected to show superior activities in various applications compared to their bulk counterparts because more active interfaces and unique compartmentation environments can be provided. Therefore, SMMs from single to multilevel structure represent a class of advanced nanostructured materials with unique structures and fascinating properties. In this Account, we highlight the progresses on the synthesis and applications of SMMs from single to multilevel architectures. The synthetic strategies have been summarized and categorized into (i) the modified Stöber method, (ii) the hydrothermal strategy, (iii) the biphase stratification approach, (iv) the nanoemulsion assembly method, (v) the evaporation induced aggregating assembly (EIAA) method, and (vi) the confined self-assembly strategy. Special emphasis is placed on the synthetic principles and underlying mechanisms for precise control of SMMs over the particle sizes, pore sizes, pore structures and functionalities as well as different levels of architectures. Moreover, the implementation performances in catalysis, drug delivery, and energy related fields have been highlighted. Finally, the opportunities and challenges for the future development of SMMs in terms of synthesis and applications are proposed.