deltaSHAPE presents a statistically rigorous approach to analyzing changes in chemical probe reactivity between two conditions. It was originally designed for finding protein binding sites using SHAPE-MaP data, which include estimated measurement errors for every nucleotide. deltaSHAPE compares reactivity differences relative to the associated errors, and also compares the magnitude of each difference relative to every other change in reactivity. Nucleotides that exhibit strong, meaningful changes in reactivity are thus identified.