In this issue, Boon et al. describe a way to electrochemically detect mismatches in DNA duplexes by sensing perturbations in base pair stacking. The method is distinct from previously reported electrocatalytic methods in that it does not rely on application of stringent hybridization conditions to prevent mismatch duplexes from forming. Instead, preformed DNA duplexes are deposited on gold electrodes, and then a redox-active methylene blue DNA intercalator inserts into the helices. If duplexes are completely base-paired the intercalator produces an electrocatalytic signal. However, the presence of a mismatch prevents charge transport and reduces the signal. The method detects even thermodynamically stable GT and GA mismatches that pose problems with hybridization-based approaches (see pp. 1042 and 1096).