Acid-sensing ion channels (ASICs), a novel family of proton-gated amiloride-sensitive cation channels, are expressed primarily in neurons of peripheral sensory and central nervous systems. Recent studies have shown that activation of ASICs, particularly the ASIC1a channels, plays a critical role in neuronal injury associated with neurological disorders such as brain ischemia, multiple sclerosis, and spinal cord injury. In normal conditions in vitro, ASIC1a channels desensitize rapidly in the presence of a continuous acidosis or following a preexposure to minor pH drop, raising doubt for their contributions to the acidosis-mediated neuronal injury. It is now known that the properties of ASICs can be dramatically modulated by signaling molecules or biochemical changes associated with pathological conditions. Modulation of ASICs by these molecules can lead to dramatically enhanced and/or prolonged activities of these channels, thus promoting their pathological functions. Understanding of how ASICs behave in pathological conditions may help define new strategies for the treatment and/or prevention of neuronal injury associated with various neurological disorders.