Members of the two-pore domain K(+) channel (K2P) family are increasingly recognized as being potential targets for therapeutic drugs and could play a role in the diagnosis and treatment of neurologic disorders. Their broad and diverse expression pattern in pleiotropic cell types, importance in cellular function, unique biophysical properties, and sensitivity toward pathophysiologic parameters represent the basis for their involvement in disorders of the central nervous system (CNS). This review will focus on multiple sclerosis (MS) and stroke, as there is growing evidence for the involvement of K2P channels in these two major CNS disorders. In MS, TASK1-3 channels are expressed on T lymphocytes and are part of a signaling network regulating Ca(2+)- dependent pathways that are mandatory for T cell activation, differentiation, and effector functions. In addition, TASK1 channels are involved in neurodegeneration, resulting in autoimmune attack of CNS cells. On the blood-brain barrier, TREK1 channels regulate immune cell trafficking under autoinflammatory conditions. Cerebral ischemia shares some pathophysiologic similarities with MS, including hypoxia and extracellular acidosis. On a cellular level, K2P channels can have both proapoptotic and antiapoptotic effects, either promoting neurodegeneration or protecting neurons from ischemic cell death. TASK1 and TREK1 channels have a neuroprotective effect on stroke development, whereas TASK2 channels have a detrimental effect on neuronal survival under ischemic conditions. Future research in preclinical models is needed to provide a more detailed understanding of the contribution of K2P channel family members to neurologic disorders, before translation to the clinic is an option.