Kainate receptors alter the excitability of mossy fiber axons and have been reported to play a role in the induction of long-term potentiation (LTP) at mossy fiber synapses in the hippocampus. These previous studies have relied primarily on the use of compounds whose selectivity is unclear. In this report, we investigate short- and long-term facilitation of mossy fiber synaptic transmission in kainate receptor knockout mice. We find that LTP is reduced in mice lacking the GluR6, but not the GluR5, kainate receptor subunit. Additionally, short-term synaptic facilitation is impaired in GluR6 knockout mice, suggesting that kainate receptors act as presynaptic autoreceptors on mossy fiber terminals to facilitate synaptic transmission. These data demonstrate that kainate receptors containing the GluR6 subunit are important modulators of mossy fiber synaptic strength.