As the century begins, natural resources are under increasing pressure, threatening public health and development. As a result, the balance between man and nature has been disrupted, with climatic changes whose effects are starting to be irreversible. Due to the relationship between the quality of the indoor built environment and its energy demand, thermal comfort issues are still relevant in the disciplinary debate. This is also because the indoor environment has a potential impact on occupants' health and productivity, affecting their physical and psychological conditions. To achieve a sustainable compromise in terms of comfort and energy requirements, several challenging questions must be answered with regard to design, technical, engineering, psychological, and physiological issues and, finally, potential interactions with other IEQ issues that require a holistic way to conceive the building envelope design. This Special Issue collected original research and review articles on innovative designs, systems, and/or control domains that can enhance thermal comfort, work productivity, and wellbeing in a built environment, along with works considering the integration of human factors in buildings' energy performance.