Classically implicated in the transport of small molecules between neighboring cells or into the extracellular milieu, emerging evidence implicates connexins and pannexins in other noncanonical biological functions. Propelled by recent technological advances and genetic approaches, this review aims to provide a comprehensive and thought-provoking perspective on unconventional functions of connexins and pannexins that could be shared with other cell surface proteins. Although multiple studies have linked dysfunctional channel activity with human disorders, the contribution of non-junctional roles of connexins and pannexins during disease pathophysiology is now beginning to blossom. We highlight the potential regulatory signals and players involved in unfamiliar connexin and pannexin activities that can pave the way to design novel therapeutic tools.