AbstractThe origin, structure, and function of the claustrum, as well as its role in neural computation, have remained a mystery since its discovery in the 17th century. Assessing the in vivo connectivity of the claustrum may bring forth useful insights with relevance to model the overall functionality of the claustrum itself. Using structural and diffusion tensor neuroimaging in N = 100 healthy subjects, we found that the claustrum has the highest connectivity in the brain by regional volume. Network theoretical analyses revealed that (a) the claustrum is a primary contributor to global brain network architecture, and that (b) significant connectivity dependencies exist between the claustrum, frontal lobe, and cingulate regions. These results illustrate that the claustrum is ideally located within the human central nervous system (CNS) connectome to serve as the putative “gate keeper” of neural information for consciousness awareness. Our findings support and underscore prior theoretical contributions about the involvement of the claustrum in higher cognitive function and its relevance in devastating neurological disease. Hum Brain Mapp 36:827–838, 2015. © 2014 Wiley Periodicals, Inc.