Memories are believed to be stored by synaptic modifications. One type of activity-dependent synaptic modification, long-term potentiation (LTP), has received considerable attention as a possible memory mechanism, particularly in hippocampus. However, use-dependent decreases in synaptic strength can store information as well. A form of homosynaptic long-term depression (LTD) has been described and widely studied in the CA1 region of the developing hippocampus in vitro. However, the relevance of this model of LTD to memory has been questioned because of failures to replicate it in the adult brain in vitro and, more recently, in vivo. Here we re-examine this important issue and find that homosynaptic LTD can in fact be elicited in the adult hippocampus in vivo, that it has all the properties described in immature CA1 in vitro, and that LTD and LTP are reversible modifications of the same Schaffer collateral synapses. Thus homosynaptic LTD is not peculiar to brain slices, nor is it only of developmental significance. Rather, out data suggest that the mechanisms of LTD and LTD may be equal partners in the mneumonic operations of hippocampal neural networks.