NMDA receptor activity is important for many physiological functions, including synapse formation and alterations in synaptic strength. NMDA receptors are composed most commonly of NR1 and NR2 subunits. There are four NR2 subunits (NR2A-NR2D). NR2 subunit expression varies across both brain regions and developmental stages. The identity of the NR2 subunit within a functional NMDA receptor helps to determine many pharmacological and biophysical receptor properties, including strength of block by external Mg2+ (Mg(o)2+). Mg(o)2+ block confers strong voltage dependence to NMDA receptor-mediated responses and is critically important for many of the functions that the NMDA receptor plays within the CNS. Here we describe the NR2 subunit dependence of the kinetics of Mg(o)2+ unblock after rapid depolarizations. We find that Mg(o)2+ unblocks from NR1/2A and NR1/2B receptors with a prominent slow component similar to that previously described in native hippocampal and cortical NMDA receptors. Strikingly, this slow component of Mg(o)2+ unblock is completely absent from NR1/2C and NR1/2D receptors. Thus currents from NR1/2C and NR1/2D receptors respond more rapidly to fast depolarizations than currents from NR1/2A and NR1/2B receptors. In addition, the slow component of Mg(o)2+ unblock from NR1/2B receptors is consistently slower than from NR1/2A receptors. This makes rapid depolarizations, such as action potential waveforms, more efficacious at stimulating Mg(o)2+ unblock from NR1/2A than from NR1/2B receptors. These NR2 subunit differences in the kinetics of Mg(o)2+ unblock are likely to help determine the contribution of each NMDA receptor subtype to current flow during synaptic activity.