Seven groups of synthetic agent, distinguished by a combination of their chemical and pharmacological characteristics exert some or all of their effects by opening plasmalemmal K+ channels primarily in smooth muscle. Progress over the past two years now allows broad structure-activity relationships to be formulated within many of the individual groups of agent. Gillian Edwards and Arthur Weston review the historical basis of these discoveries and comment on the significance of new developments. They focus on the search for tissue and channel selectivity, two factors likely to be important for the successful clinical deployment of these substances as antihypertensive and bronchodilator agents.