High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders. However, understanding of the mechanisms responsible for the therapeutic action of DBS remains elusive. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity. Using the results from functional imaging, neurochemistry, neural recording, and neural modeling experiments we address the general hypotheses and attempt to reconcile what have been considered conflicting results from these different research modalities. Our analysis suggests stimulation-induced modulation of pathological network activity represents the most likely mechanism of DBS; however, several open questions remain to explicitly link the effects of DBS with therapeutic outcomes.