This review gives some indication of the progress that has been made in understanding synaptic transmission by use of new methods for measuring and controlling presynaptic [Ca2+]i. Many unsolved problems remain. We still do not have a clear idea of the exact relationship between [Ca2+]i and transmitter release and whether this relationship is the same under all circumstances. The apparently different [Ca2+]i-dependence of evoked transmitter release and of PTP suggest multiple molecular sites of calcium action that remain to be identified. A complete and comprehensive model of transmitter release has yet to be devised, and questions raised by our experiments may indicate that it is still too early to try to construct a precise model. We also do not know just how serotonin acts to modulate transmitter release, only that it does not appear to alter either resting or entering calcium. Some of these questions may be approachable with the techniques described here; others are not and require different methods for their resolution. The work continues.