A systematic analysis of one-to-one chemical replacements occurring in a set of 50,000 druglike molecules was performed. The frequency of occurrence, as well as the average change in measured and calculated properties, was computed for each observed substitution. The experimental properties considered were solubility, protein binding, and logD. The calculated properties were logP, molecular weight, number of hydrogen bond donors and acceptors, and polar surface area. During this analysis, in which 9000 different functional groups were considered, 0.7 million substitutions were identified and stored in a database. As an application, we present a web interface from which users can identify historically observed replacements of any functional group on their query molecule. The server returns a list of side-chains, as well as the historically observed shift in experimental properties.