Abstract Motivation The difficulty to find new drugs and bring them to the market has led to an increased interest to find new applications for known compounds. Biological samples from many disease contexts have been extensively profiled by transcriptomics, and, intuitively, this motivates to search for compounds with a reversing effect on the expression of characteristic disease genes. However, disease effects may be cell line-specific and also depend on other factors, such as genetics and environment. Transcription profile changes between healthy and diseased cells relate in complex ways to profile changes gathered from cell lines upon stimulation with a drug. Despite these differences, we expect that there will be some similarity in the gene regulatory networks at play in both situations. The challenge is to match transcriptomes for both diseases and drugs alike, even though the exact molecular pathology/pharmacogenomics may not be known. Results We substitute the challenge to match a drug effect to a disease effect with the challenge to match a drug effect to the effect of the same drug at another concentration or in another cell line. This is welldefined, reproducible in vitro and in silico and extendable with external data. Based on the Connectivity Map (CMap) dataset, we combined 26 different similarity scores with six different heuristics to reduce the number of genes in the model. Such gene filters may also utilize external knowledge e.g. from biological networks. We found that no similarity score always outperforms all others for all drugs, but the Pearson correlation finds the same drug with the highest reliability. Results are improved by filtering for highly expressed genes and to a lesser degree for genes with large fold changes. Also a network-based reduction of contributing transcripts was beneficial, here implemented by the FocusHeuristics. We found no drop in prediction accuracy when reducing the whole transcriptome to the set of 1000 landmark genes of the CMap’s successor project Library of Integrated Network-based Cellular Signatures. All source code to re-analyze and extend the CMap data, the source code of heuristics, filters and their evaluation are available to propel the development of new methods for drug repurposing. Availability https://bitbucket.org/ibima/moldrugeffectsdb Contact steffen.moeller@uni-rostock.de Supplementary information Supplementary data are available at Briefings in Bioinformatics online.