Mitochondrial potassium channels play an important role in cytoprotection. The following potassium channels have been described in the inner mitochondrial membrane: the ATP-regulated potassium channel, the large conductance calcium activated potassium channel, the voltage-gated potassium channel and the twin-pore domain TASK-3 potassium channel. Potassium channels in the inner mitochondrial membrane are modulated by inhibitors and activators (potassium channel openers) previously described for plasma membrane potassium channels. The majority of mitochondrial potassium channel modulators exhibit a broad spectrum of off-target effects. These include uncoupling properties, inhibition of the respiratory chain and effects on cellular calcium homeostasis. Therefore, the rational application of channel inhibitors or activators is crucial to understanding the cellular consequences of mitochondrial channel inhibition or activation. In this paper, new observations on mitochondrial potassium channel will be discussed: 1). their molecular identity, 2). their interaction with potassium channel openers and inhibitors and 3). their functional role.