Calcium ions (Ca 2+ ) play a critical role in triggering neurotransmitter release. The rate of release is directly related to the concentration of Ca 2+ at the presynaptic site, with a supralinear relationship. There are two main sources of Ca 2+ that trigger synaptic vesicle fusion: influx through voltage-gated Ca 2+ channels in the plasma membrane and release from the endoplasmic reticulum via ryanodine receptors. This chapter will cover the sources of Ca 2+ at the presynaptic nerve terminal, the relationship between neurotransmitter release rate and Ca 2+ concentration, and the mechanisms that achieve the necessary Ca 2+ concentrations for triggering synaptic exocytosis at the presynaptic site.