In recent years, the application of the principles of human factors has revealed the need for rethinking the whole indoor built environment design. Indoor environments should be livable, comfortable, safe, and productive, with low energy costs, and their design has to be compliant with sustainability requirements. This is also because the indoor environment has a potential impact on occupants’ health and productivity, affecting their physical and psychological conditions. In this context, the design and assessment of indoor thermal comfort, although regulated by a robust framework of standards, require a novel approach to find the best solution under the specific context every time. This implies general rules to be respected and the awareness that a project of comfort is a project that ultimately puts people and their needs at the center. This Special Issue deals with most debated challenges in the field of thermal comfort with a special focus on 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. Covered topics include the following: fundamentals in thermal comfort and IEQ assessment; field investigations; innovative designs, systems, and/or control domains that can enhance thermal comfort; and the integration of human factors in buildings’ energy performance. We thank all authors for their submissions, and we also thank the colleagues involved in the review process of received manuscripts.