Chronic changes in the level of neuronal activity (over a period of days) trigger compensatory changes in synaptic function that seem to contribute to the homeostatic restoration of neuronal activity. Changes in both quantal amplitude and vesicle release contribute to homeostatic synaptic plasticity, but they are often considered as the same phenomenon. In this review, we propose a new approach to studying how neuronal activity is sensed and changes in synaptic function are expressed during synaptic compensation. Changes in quantal amplitude and vesicle release should be considered separately in an attempt to identify the sensors that trigger homeostatic synaptic plasticity. Although data are limited, current evidence suggests that the sensors triggering changes in the quantal amplitude and vesicle release exist at different locations. Furthermore, it is important to recognize that at least two different mechanisms underlie changes in quantal amplitude during homeostatic synaptic plasticity: changes in both the number of postsynaptic receptors and loading of synaptic vesicles with neurotransmitter. Finally, modulation of the probability of neurotransmitter release contributes to the changes in vesicle release associated with homeostatic synaptic plasticity. An improved understanding of where and how neuronal activity is sensed, in addition to the types of changes in synaptic function that are induced, will be needed both to design future experiments and to understand the consequences of synaptic compensation following injury to the nervous system.