Over the last decades, cardiovascular disease has become the primary cause of death in the Western world, and this trend is expanding throughout the world. In particular, atherosclerosis and the subsequent vessel obliterations are the primary cause of ischemic disease (stroke and coronary heart disease). Excess calcium influx into the cells is one of the major pathophysiological mechanisms important for ischemic injury in the brain and heart in humans. The large-conductance calcium-activated K(+) channels (BK) are thus interesting candidates to protect against excess calcium influx and the events leading to ischemic injury. Indeed, the mitochondrial BK channels (mitoBK) have recently been shown to play a protective function against ischemia-reperfusion injury both in vitro and in animal models, although the exact mechanism of this protection is still under scrutiny. In addition, in both the plasma membrane and mitochondrial BK channel, the α-subunit itself is sensitive to hypoxia. This sensitivity is tissue specific and conferred by a highly conserved motif within an alternatively spliced cysteine-rich insert (STREX) in the intracellular C terminus of the channel. This review describes recent developments of the increasing relevance of BK channels in hypoxia and ischemia-reperfusion injury.