There is growing evidence that neurotransmitters can be released not only by exocytosis but also through the membrane carriers responsible for transmitter re-uptake. Giulio Levi and Maurizio Raiteri review the in vitro and in vivo evidence supporting the existence of a carrier-mediated release for different classes of transmitters. While the physiological significance of carrier-mediated release remains speculative, widely used drugs such as sympathomimetic amines, the anorectic drug fenfluramine and some drugs of abuse act in part by stimulating monoamine carrier-mediated release. Moreover, antidepressants known to inhibit monoamine reuptake, can block carrier-mediated release. This mechanism may also come into play in pathological conditions such as ischaemia.