CA1 pyramidal neurons are the final integrators of information flow leaving the hippocampus, yet are singularly vulnerable to activity-dependent cell death. Zinc (Zn) entry into cells may add to this vulnerability. Here, we find thatSlc39a1andSlc39a3, members of theZip(Zrt/Irt-like protein) plasmalemmal Zn transporter family, are predominantly expressed in the hippocampus. We examinedZip-1,3-deficient mice to investigate their role in neurodegeneration following intense synaptic activation. When isolated by blockade of NMDA receptors and voltage-gated calcium channels, the absence of both transporters slowed passive Zn uptake into CA1 neurons measured with intracellular fluorescent Zn dyes.In vivoCA1 cell damage following kainic acid exposure was greatly attenuated. Consistent with the hypothesis that Zn entry contributes to neurodegeneration,Znt-3-deficient mice lacking synaptic Zn also show less hippocampal cell damage following kainic acid injection.Ziptransporters may provide selective therapeutic targets to protect these neurons from early Zn-induced neurodegeneration following injury.