The synapse made by hippocampal mossy fibers onto pyramidal neurons of hippocampal area CA3 displays a form of long-term potentiation (LTP) that is independent of the activation of NMDA receptors. Considerable controversy exists as to whether the induction of mossy fiber LTP requires postsynaptic activation and, thus, whether mossy fiber LTP is Hebbian or non-Hebbian. Here we report the induction of both Hebbian and non-Hebbian forms of long-term potentiation at the mossy fiber-CA3 synapse in in vitro slice preparation. These two forms of potentiation can be induced selectively by different induction conditions. Sustained presynaptic activation is sufficient to induce the non-Hebbian form of mossy fiber LTP, whereas brief presynaptic activation coincident with postsynaptic depolarization is required to induce the Hebbian form. We suggest that non-Hebbian forms of plasticity may play an important role in dynamically regulating the thresholds for inducing Hebbian forms of plasticity.