The late, transcription- and translation-dependent phase of long-term synaptic potentiation (L-LTP) at the Schaffer collateral synapse of the hippocampus is an experimental model of the synaptic plasticity underlying long-lasting memory formation. L-LTP is typically induced by homosynaptic tetanic stimulation; but associative forms of learning are likely to require the heterosynaptic pairing of stimuli. Here we describe L-LTP elicited by such heterosynaptic pairing at the Schaffer collateral synapse in mice. We find that repeated stimulation of one pathway at low frequency (0.2 Hz), which does not by itself induce synaptic potentiation, will produce long-lasting synaptic plasticity when paired with a brief conditioning burst applied to an independent afferent pathway. The induction of heterosynaptic L-LTP is associative and critically depends on the precise time interval of pairing: simultaneous, conjunctional pairing induces L-LTP; in contrast, delayed pairing induces short-lasting early-phase LTP. Heterosynaptically induced early-phase LTP could be depotentiated by repeatedly presenting unpaired test stimuli, whereas L-LTP could not. This heterosynaptically induced L-LTP requires PKA and protein synthesis. In addition, heterosynaptically induced L-LTP is impaired in transgenic mice that express KCREB (a dominant negative inhibitor of adenosine 3'5'-cyclic monophosphate response element-binding protein-mediated transcription) in the hippocampus. These mice have previously been shown to be impaired in spatial memory but have normal L-LTP as induced by a conventional homosynaptic tetanic protocol. These data suggest that at least in some instances this L-LTP-inducing protocol may better model behaviorally relevant information storage and the in vivo mechanisms underlying long-lasting memories.