At fast CNS synapses, the role of asynchronous release following initial synchronous release is poorly understood. We examined the contribution of asynchronous release to GABAergic transmission in the cochlear nucleus across a 40-fold range of electrical stimulus frequencies. Whereas quantal release was highly synchronized at low frequencies, it was largely continuous and desynchronized at high frequencies. Despite the change in release mode, intense and steady inhibitory transmission was virtually maintained. Experimental analyses and modeling studies indicated that this "desynchronization" process was dependent on presynaptic Ca2+ accumulation, facilitation of vesicle release, and short-term depletion of available vesicles. Asynchronous release at high frequencies may help generate a smooth inhibitory "tone" by minimizing the consequences of random timing of presynaptic action potentials.