Strategies to detect small genetic differences have employed DNA ligase enzymes in sequence detection because the enzymes are very sensitive to base mismatches at the ligation junction, but the enzymes show low activity with RNA and have other limitations. On page 148, Xu et al. describe the coupling of fluorescent reporter probes in a nonenzymatic, phosphorothioate–iodide ligation reaction for mutation detection. They demonstrate that the ligation reaction is able to detect sequences on both DNA and RNA templates, and that it works well in different formats such as in solution or on gels. Because it requires no enzyme, the approach may be useful in intact cells or tissues, although this remains to be determined.