Hemichannels, which are one half of the gap junction channels, have independent physiological roles. Although hemichannels consisting of connexins are more widely documented, hemichannels of pannexins, proteins homologous to invertebrate gap junction proteins also have been studied. There are at least 21 different connexin and three pannexin isotypes. This variety in isotypes results in tissue-specific hemichannels, which have been implicated in varied events ranging from development, cell survival, to cell death. Hemichannel function varies with its spatio-temporal opening, thus demanding a refined degree of regulation. This review discusses the activity of hemichannels and the molecules released in different physiological states and their impact on tissue functioning. © 2012 John Wiley & Sons, Ltd.