The procedure of drug approval is time-consuming, costly and risky. Accidental findings regarding multi-specificity of approved drugs led to block-busters in new indication areas. Therefore, the interest in systematically elucidating new areas of application for known drugs is rising. Furthermore, the knowledge, understanding and prediction of so-called off-target effects allow a rational approach to the understanding of side-effects. With PROMISCUOUS we provide an exhaustive set of drugs (25 000), including withdrawn or experimental drugs, annotated with drug–protein and protein–protein relationships (21 500/104 000) compiled from public resources via text and data mining including manual curation. Measures of structural similarity for drugs as well as known side-effects can be easily connected to protein–protein interactions to establish and analyse networks responsible for multi-pharmacology. This network-based approach can provide a starting point for drug-repositioning. PROMISCUOUS is publicly available at http://bioinformatics.charite.de/promiscuous.