Quantal size is often modeled as invariant, although it is now well established that the number of transmitter molecules released per synaptic vesicle during exocytosis can be modulated in central and peripheral synapses. In this review, we suggest why presynaptically altered quantal size would be important at social synapses that provide extrasynaptic neurotransmitter. Current techniques used to measure quantal size are reviewed with particular attention to amperometry, the first approach to provide direct measurement of the number of molecules and kinetics of presynaptic quantal release, and to CNS dopamine neuronal terminals. The known interventions that alter quantal size at the presynaptic locus are reviewed and categorized as (1) alteration of transvesicular free energy gradients, (2) modulation of vesicle transmitter transporter activity, (3) modulation of fusion pore kinetics, (4) altered transmitter degranulation, and (5) changes in synaptic vesicle volume. Modulation of the number of molecules released per quantum underlies mechanisms of drug action of L-DOPA and the amphetamines, and seems likely to be involved in both normal synaptic modification and disease states. Statistical analysis for examining quantal size and data presentation is discussed. We include detailed information on performing nonparametric resampling statistical analysis, the Kolmogorov-Smirnov test for two populations, and random walk simulations using spreadsheet programs.