The study of compound promiscuity is a hot topic in medicinal chemistry and drug discovery research. Promiscuous compounds are increasingly identified, but the molecular basis of promiscuity is currently only little understood. Utilizing the matched molecular pair formalism, we have analyzed patterns of compound promiscuity in a publicly available small molecule microarray data set. On the basis of our analysis, we introduce "promiscuity cliffs" as pairs of structural analogs with single-site substitutions that lead to large-magnitude differences in apparent compound promiscuity involving between 50 and 97 unrelated targets. No substructures or substructure transformations have been detected that are generally responsible for introducing promiscuity. However, within a given structural context, small chemical replacements were found to lead to dramatic promiscuity effects. On the basis of our analysis, promiscuity is not an inherent feature of molecular scaffolds but can be induced by small chemical substitutions. Promiscuity cliffs provide immediate access to such modifications.