The emerging new field of research on Tactile Internet with Human-in-the-Loop (TaHiL) aims to achieve significant breakthroughs to enhance collaborations between humans and machines or-more generally, Cyber-Physical System (CPS)-in real, virtual, and remote environments. The vision of TaHiL is to enable humans to interact with cooperating CPS over intelligent wide-area communication networks to promote equitable access to remote work, medical, learning, social, and recreational opportunities for people of different ages, genders, cultural backgrounds, or physical limitations. Thus reaching far beyond the current state of the art in digitalization and human-machine interaction, the long-term goal of the research on TaHiL is to democratize the access to skills and expertise the same way as the current Internet has democratized the access to information. Capitalizing on recent advancements in the fields of telecommunication, electrical and material engineering, computer science, robotics, psychology, cognitive neuroscience, and medicine, researchers in this new transdisciplinary field are pursuing basic and applied research to (i) advance the understanding about complex dynamics of human goal-directed multisensory perception and action from the psychological, neurocognitive, medical, and computational perspectives; (ii) develop novel sensor and actuator technologies that augment the human mind and body; (iii) develop fast, bendable, adaptive, and reconfigurable electronics; (iv) create intelligent communication networks that connect humans and CPS by continuously adapting and learning to provide low latency, as well as high levels of resilience and security; (v) design new haptic coding schemes to cope with the deluge of information from massive numbers of body sensors; (vi) design online learning mechanisms as well as interface solutions for machines and humans to predict and augment each other’s actions; and (vii) to evaluate the above technological solutions as well as to engage the general public about the potential possibilities and concerns that the new technologies will bring. The research on TaHiL will be essential for diverse applications involving human-machine interactions, including, most notably, in medicine, industry, and the Internet of Skills (IoS). This overview chapter highlights the challenges, directions, programmatic structures and application domains of the new transdisciplinary research endeavor of TaHiL. Key building blocks of TaHiL are presented in details in the 15 subsequent chapters collected in this volume.