Aim: Deficient glutamate reuptake occurs in the cerebral cortex of Huntington’s disease (HD) patients and murine models. Here we examine the effects of partial or complete blockade of glutamate transporters on excitatory postsynaptic currents (EPSCs) of cortical pyramidal neurons (CPNs). Methods: Whole-cell patch clamp recordings of CPNs in slices from symptomatic R6/2 mice and wildtype (WT) littermates were used to examine the effects of selective or concurrent inhibition of glutamate reuptake transporters. Results: Selective inhibition of the glial glutamate transporter 1 (GLT-1) or the glutamate aspartate transporter (GLAST) produced slight decreases in decay time of evoked EPSCs in CPNs from WT and R6/2 mice with no significant differences between genotypes. In contrast, concurrent inhibition of both transporters with DL-TBOA induced a significant increase in area and decay time and this effect was significantly greater in R6/2 CPNs. Furthermore, full blockade also reduced spontaneous EPSC frequency and exacerbated epileptiform activity in CPNs from symptomatic R6/2 mice. Conclusions: R6/2 CPNs are more sensitive to glutamate accumulation during full inhibition of both glutamate transporters and these neurons have homeostatic mechanisms to cope with inhibition of GLT-1 or GLAST by a mechanism that involves upregulation of either transporter when the other is deficient.