Glutamate signaling in the auditory brainstem is a dynamic process. It involves the perfect coordination of pre- and postsynaptic factors that reliably permit the transfer of information between neurons. When compared to other brain regions, glutamate signaling in the auditory brainstem is unique in that it provides the initial mechanisms underlying the perception of behaviorally relevant communication signals. Disruptions in such mechanisms are thought to underlie several hearing-related disorders. Relying on the foundation of work by Dr. Edwin Rubel and colleagues, this chapter offers a conceptual overview of factors that regulate glutamate signaling in the auditory brainstem, as well as determinants responsible for development, activity-dependent regulation, pathophysiology, and neuromodulation.