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Herein, we report mismatch\u2010exchange as a new design principle that allows the highly sensitive and robust discrimination of single nucleotide polymorphisms (SNPs) by simply manipulating the number and position of mismatches in both probes and the reaction products. Leveraging mismatches to drive the strand\u2010exchange and finetuning the specificity, mismatch\u2010exchange is particularly advantageous for analyzing complex nucleic acid targets containing multiple nearby SNPs. Both selective tolerance to synonymous SNPs and OR\u2010gate\u2010based detection of clustered drug\u2010resistant SNPs were demonstrated. 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