The brief time course of the calcium (Ca²⁺) channel opening combined with the molecular-level colocalization of Ca²⁺ channels and synaptic vesicles in presynaptic terminals predict sub-millisecond calcium concentration ([Ca²⁺]) transients of 100 µM in the immediate vicinity of the vesicle. This [Ca²⁺] is much higher than some of the recent estimates for the equilibrium dissociation constant of the Ca²⁺ sensor(s) that control neurotransmitter release suggesting release should be close to saturation, yet it is well known that release is highly sensitive to changes in Ca²⁺ influx. We show that due to the brevity of the Ca²⁺ influx the binding kinetics of the Ca²⁺-sensor rather than its equilibrium affinity determine receptor occupancy. For physiologically relevant Ca²⁺ currents and forward Ca²⁺ binding rates the effective affinity of the Ca²⁺-sensor can be several-fold lower than the equilibrium affinity. Using simple models, we show redundant copies of the binding sites increase effective affinity of the Ca²⁺ sensor for release. Our results predict that different levels of expression of Ca²⁺ binding sites could account for apparent differences in Ca²⁺ sensor affinities between synapses. Using Monte Carlo simulations of Ca²⁺ dynamics with nanometer resolution we demonstrate that these kinetic constraints combined with vesicles acting as diffusion barriers prevent saturation of the Ca²⁺-sensor(s) for neurotransmitter release. We further show the random positioning of the Ca²⁺-sensor molecules around the vesicle can result in the emergence of two distinct populations of the vesicles with low and high release probability. These considerations allow experimental evidence for the Ca²⁺ channel-vesicle colocalization to be reconciled with a high equilibrium affinity for the Ca²⁺-sensor of the release machinery.