Important roles for connexins have emerged from studies linking connexin mutations to human disease. Use of connexins tagged with GFP have provided a clearer picture of the mechanisms that govern connexin channel function and it is now evident that functional forms of connexin channel include cell-cell channels and unapposed hemichannels. Clustering appears to be a requirement for opening of cell-cell channels and suggests that dynamic changes occur in plaques (clusters) as they form and grow that are critical for channel function. In particular, recruitment or generation of ‘silent’ channels has gained support as a mechanism by which coupling can be dynamically regulated within formed plaques. Two distinct voltage sensitive gating mechanisms appear to be built -into each hemichannel, one putatively located at the cytoplasmic entrance and the other at the extracellular end, each differing in sensitivity, kinetics and degree of channel/hemichannel closure. The extracellular gate may also be that whic h opens unapposed hemichannels in the plasma membrane and be the final target of many known chemical agents that act as uncouplers of cell-cell communication. An understanding of the structural requirements for regulation via gating and clustering represents an important preclinical step in the design of therapeutic agents to treat disorders arising from connexin channel and hemichannel dysfunction.