The acute effects of Pb++, Cd++ and Hg++ have been studied on the amphibian neuromuscular junction. These heavy metal ions primarily affect those presynaptic mechanisms which underlie neurotransmitter release; no significant postsynaptic effects were observed. All experiments were performed on the isolated sciatic nerve/sartorius muscle preparation. Conventional electrophysiological techniques using intracellular recordings were used to monitor acetylcholine (ACh) release. Ringer solutions usually contained high Mg++ and low Ca++ concentrations so that endplate potentials (EPPs) could be recorded under contraction-free conditions. Pb++, Cd++ and Hg++ were added to the Ringer solutions as chloride salts. Of the two forms of transmitter release, Pb++ blocked one (evoked release or EPP amplitude) and stimulated the other (the rate of spontaneous release or MEPP frequency). When a preparation was first exposed to a moderate dose of Pb++, the EPP amplitude decreased within about 1-2 min; however, at that time, the MEPP frequency was just beginning to increase. Low concentrations of Pb++ often reduced the EPP greatly without altering the MEPP frequency. Evidence is provided for a competitive interaction between Pb++ and Ca++ ions in evoked release which is believed to occur on the extracellular side of the nerve terminal. The dissociation constant between Pb++ and the presynaptic Ca++ receptor is about 1 microM. The increase in MEPP frequency is assumed to be due to an intracellular action of Pb++ which may reduce the ability of nerve terminal organelles to sequester Ca++ and thereby increase the intracellular concentration of ionized Ca++. Cd++ also blocks evoked ACh release by a competitive inhibitory mechanism similar to that for Pb++. Cd++ is slightly less potent than Pb++, the dissociation constant for Cd++ being around 2.8 microM. In contrast to Pb++, Cd++ does not increase resting MEPP frequency. Hg++ is unique in that it first causes an increase in evoked ACh release and then a sudden and complete blockade; the MEPP frequency follows a similar time course. The mechanism underlying these effects of Hg++ is uncertain.