It has been hypothesized that the direction of synaptic weight change elicited by synaptic activity depends on the magnitude of the activity-dependent rise in intracellular Ca2+ concentration. Several aspects of this hypothesis were examined at the Schaffer collateral CA1 synapse, where both long-term depression (LTD) and long-term potentiation (LTP) can be elicited and are Ca2+ dependent. Brief tetanic stimulation, which normally generated LTP, could induce LTD when Ca2+ entry via NMDA receptors was limited either by moderate concentrations of D-APV or by voltage clamping cells at negative membrane potentials. Repetitive activation of voltage-dependent Ca2+ channels in the absence of afferent stimulation could also elicit an LTD that was Ca2+ dependent and was occluded by prior generation of homosynaptic LTD using prolonged low evidence that the minimal requirements for inducing LTD involve simply a transient influx of Ca2+ into the postsynaptic cell, via either NMDA receptors or voltage-dependent Ca2+ channels.