It is textbook knowledge that the extracellular proton concentration is maintained constant within a narrow range. It is now clear, however, that protons perform useful work as an extracellular transmitter: synaptic vesicles contain protons in approximately 100-fold higher concentrations (pH 5.5) than the extracellular space (pH 7.4). Accordingly, protons are released together with the content of synaptic vesicles and protons can be viewed as a ubiquitous co-transmitter of most other neurotransmitters. In addition, an ischemia, for example during inflammation, is generally accompanied by an acidosis (pH 7.3 – 6.7). Such an acidosis can elicit or enhance pain. The transient acidosis accompanying neurotransmission as well as the persistent acidosis accompanying an ischemia are sensed by diverse receptor molecules. Among the most sensitive receptors for extracellular protons are the acid-sensing ion channels (ASICs). ASICs are broadly expressed in neurons of the central and the peripheral nervous system. They are activated by a drop in pH below pH 6.9. Usually, ASICs respond with a desensitizing current, but modest acidification can also elicit a sustained ASIC current. In the central nervous system, ASICs probably have a postsynaptic localization and in the peripheral nervous system they localize to the sensory endings of nociceptors. Thus, ASICs are ideally suited to sense fluctuations of the extracellular pH both during neurotransmission and sensory transduction. In my talk, I will introduce into the physiology and pathophysiology of ASICs. Moreover, I will present some of our results addressing the mechanism by which protons activate ASICs.