There is a dearth of chemical inhibitors of connexin-mediated intercellular communication. The advent of short "designer" connexin mimetic peptides has provided new tools to inhibit connexin channels quickly and reversibly. This perspective describes the development of mimetic peptides, especially Gap 26 and 27 that are the most popular and correspond to specific sequences in the extracellular loops of connexins 37, 40 and 43. Initially they were used to inhibit gap-junctional coupling in a wide range of mammalian cells and tissues. Currently, they are also being examined as therapeutic agents that accelerate wound healing and in the early treatment of spinal cord injury. The mimetic peptides bind to connexin hemichannels, influencing channel properties as shown by lowering of electrical conductivity and potently blocking the entry of small reporter dyes and the release of ATP by cells. A mechanism is proposed to help explain the dual action of connexin mimetic peptides on connexin hemichannels and gap-junctional coupling.