Cortical plasticity seems to be critical for the establishment of permanent memory traces^,,. Little is known, however, about the molecular and cellular processes that support consolidation of memories in cortical networks^,. Here we show that mice heterozygous for a null mutation of α-calcium-calmodulin kinase II (α-CaMKII^+/-) show normal learning and memory 1–3 days after training in two hippocampus-dependent tasks. However, their memory is severely impaired at longer retention delays (10–50 days). Consistent with this, we found that α-CaMKII^+/- mice have impaired cortical, but not hippocampal, long-term potentiation. Our results represent a first step in unveiling the molecular and cellular mechanisms underlying the establishment of permanent memories, and they indicate that α-CaMKII may modulate the synaptic events required for the consolidation of memory traces in cortical networks.