A web tool for the detection of significant enrichment and depletion of combinations of annotations is presented. Annotation-Modules accepts 12 different input IDs, allows free selection of the reference genes and the upload of pre-annotated gene lists. It offers an improvement over the current tools in two critical aspects. First, the underlying annotation database implements features from many different fields like gene regulation and expression, sequence properties, evolution and conservation, genomic localization and functional categories-resulting in about 60 different annotation features. Second, it examines not only single annotations but also all the combinations, which is important to gain insight into the interplay of different mechanisms in the analyzed biological system.