There are several reasons that one might want to selectively do away with gap junction channels. Of critical importance to electrophysiologists, coupling interferes with isopotentiality, a requirement for voltage-clamping cells. Second, by measuring the function of cell groups or tissues in which gap junctions have been eliminated, it may be possible to infer the roles that gap junctions normally play (“negative” physiology: refs. 1–5). Finally, there are pathological conditions in which gap junction overexpression might be an underlying cause (or problematic consequence) of the pathology, and therefore gap junction blockers might be therapeutically useful. Despite the desirability of finding agents that would specifically block intercellular communication, however, there is as yet no “silver bullet” that will close gap junction channels without side effects and, as considered later, some of the most commonly used gap junction blockers do not totally close the channels, but only partially impair their conductance.