The possible biological significance of low concentrations of Cu2+ on the guinea-pig ileum has been investigated. Responses to nerve stimulation by single electrical shocks, acetylcholine (ACh), and histamine and the response to ACh of depolarized muscle were examined. In summary, Cu2+ has diverse and dose-dependent effects on the ileum. A stimulant effect dominates in intestine accommodated in physiological saline solution. The excitatory effect of the ion, in the concentration range 10 nM-1 microM, is probably due to stimulation of a depolarization-coupled initiation of the contraction. The inhibitory effect of Cu2+ (10 nm-1 microM) is presumably due to a decreased Ca2+ availability for the contractile process. In a higher concentration range (10 microM-100 microM) the stimulant action could also, in part, be related to a copper-induced release of Ca2+ from a storage site. No effect that certainly could be ascribed to a neuronal site of action could be observed. The possible effect of Cu2+, released during corrosion of dental alloys, on oral excitable tissue such as taste and pain receptors is discussed.