Because of the physiological role played by the hyperpolarisation process resulting from a K+ outflow, it is not surprising that compounds able to activate outward K+ channels are considered as promising drugs, with exciting perspectives for the treatment of several cardiovascular, respiratory, neurological and urological diseases. Among the different and numerous K+ channel families, medicinal chemistry has focused its major interest onto two channel types: the ATP-sensitive channels (KATP) and the large conductance subtype (BK), that belongs to the wide family of calcium-activated K+ channels. BK channels are almost ubiquitous and exhibit single channel conductance of 100-300 pS, a property which justifies the potent role of these channels in the control of the membrane potential. BK channels have been investigated as potential therapeutic targets for different neuropathies, because of their profound influence on the neuronal activity. Moreover, BK channels are expected to have applications for the therapy of cardiovascular diseases. A potent feed-back control of the vascular and non-vascular smooth muscle tone is mediated by these channels, whose activation can be promoted by both a rise of the intracellular free calcium concentration as well as a membrane depolarisation. Additionally, BK channel activation can also be induced by other factors, such as cAMP-mediated phosphorylation, Gproteins, GMP and cGMP. The aim of this paper is to give a concise overview of the biological and pharmacological properties and potential therapeutic applications of activators of BK channels present at the vascular level. The ”state of the art“ in the pharmaceutical development of natural and synthetic BKactivators, with a description of the lead chemical structures, will be also described.