A brief historical background on synaptic transmission in relation to Ca2+ dynamics and short-term facilitation is described. This study focuses on the mechanisms responsible for the regulation of intracellular calcium concentration ([Ca2+]i) in high output terminals of larval Drosophila compared to a low-output terminal of the crayfish neuromuscular junction (NMJ). Three processes; plasmalemmal Na+/ Ca2+ exchanger [NCX], Ca2+-ATPase (PMCA), and sarcoplasmic/endoplasmic Ca2+-ATPase (SERCA) are important in regulating the [Ca2+]i are examined. When the NCX is compromised by reduced [Na+]o, no consistent effect occurred; but a NCX blocker KB-R7943 decreased the excitatory postsynaptic potential (EPSP) amplitudes. Compromising the PMCA with pH 8.8 resulted in an increase in EPSP amplitude but treatment with a PMCA specific inhibitor carboxyeosin produced opposite results. Thapsigargin exposure to block the SERCA generally decreases EPSP amplitude. Compromising the activity of the above Ca2+ regulating proteins had no substantial effects on short-term depression. The Kum170TS strain (with dysfunctional SERCA), showed a decrease in EPSP amplitudes including the first EPSP within the train. Synaptic transmission is altered by reducing the function of the above three [Ca2+]i regulators; but they are not consistent among different species as expected. Results in crayfish NMJ were more consistent with expected results as compared to the Drosophila NMJ. It is predicated that different mechanisms are used for regulating the [Ca2+]i in high and low output synaptic terminals.