The physiological role of K + channel opening by endogenous substances (e.g., neurotransmitters and hormones) is a recognised inhibitory mechanism. Thus, the identification of novel synthetic molecules that directly open K + channels has led to a new direction in the pharmacology of ion channels. The existence of many different subtypes of K + channels has been an impetus in the search for new molecules demonstrating channel and, thus, tissue selectivity. This review focuses on the different classes of openers of K + channels, the intracellular mechanisms involved in the execution of their effects, and potential therapeutic targets.