Large-conductance Ca2+-activated K+ (BK-Ca) channels differ from most of other K+ channels in that their activation is under dual control, i.e., activated by either increase in intracellular Ca2+ or membrane depolarization. These channels, which are widely distributed in a variety of cells, can control Ca2+ influx as well as a number of Ca2+-dependent physiological processes. In neurons or neuroendocrine cells, BK-Ca channels are believed to play an important role in controlling hormonal secretion by altering the duration and frequency of action potentials. The activity of BK-Ca channels functionally expressed in vascular endothelial cells can control K+ efflux and affect intracellular Ca2+ concentration. Experimental observations have revealed that a variety of compounds can directly modulate BK-Ca channel activity. Epoxyeicosatrienoic acids, a metabolite of arachidonic acid, and the increase in intracellular cyclic GMP with vinpocetine or YC-1 can stimulate BK-Ca channel activity. The increased activity of BK-Ca channels thus serves as a negative feedback mechanism to limit Ca2+ influx in excitable cells. Clotrimazole, an imidazole P-450 inhibitor used for the management of sickle cell anemia, can directly suppress BK-Ca channel activity. Riluzole, a drug used for the treatment of amyotrophic lateral sclerosis, can directly enhance channel activity in neuroendocrine cells. This effect may explain its inhibitory action on excitatory neurotransmission. 2-Methoxyestradil, an endogenous metabolite of 17β-estradiol, suppresses BK-Ca channel activity, whereas resveratrol, a natural phytoalexin present in grapes and wine, directly stimulates BK-Ca channel activity in vascular endothelial cells. These effects may be responsible for their actions on functional activities of endothelial cells. The fenamates, a family of nonsteroidal anti-inflammatory drugs, are also openers of BK-Ca channels. Therefore, the modulation of BK-Ca channel activity in excitable and non-excitable cells can be important for therapeutic interventions.