A proportion of small diameter primary sensory neurones innervating human skin are chemosensitive. They respond in a receptor dependent manner to a range of substances including neurotransmitters, inflammatory mediators, algogens, thermogens and pruritogens. Interestingly, both the terminals and axons of unmyelinated C-fibres are chemosensitive and exposure of either to chemical agents may result in the generation of action potentials and/or a more subtle modulation of excitability. Using electrophysiological techniques, the chemosenstivity of human peripheral axons has recently been examined. In vitro assessment of human sural nerve indicates that a distinct population of C-fibre afferents is depolarized by GABA acting via GABAA receptors. This provides supportive evidence from human tissue for the idea that GABA may presynaptically modulate peripheral C-fibre input to the spinal dorsal horn and potentially regulate the onset and progression of chronic neuropathic pain states. Electrophysiological techniques have also recently been employed to compare human sural nerve A-fibre responses in vitro A-fibre recordings from the median nerve in healthy subjects before and after an oral dose of the analgesic compound flupirtine. Flupritine enhances the opening of slowly-activating KV7 channels and the effects of a single clinical dose can be detected in peripheral A-fibres as a shortening of the relative refractory period and a curtailing of ectopic induced following ischaemia. Electrophysiological assessment of A- and C-fibre axons in human peripheral nerve provides insight into both the physiological and therapeutic potential of axonal chemosensitivity.