MOTIVATION: Gene set analysis has revolutionized the interpretation of high-throughput transcriptomic data. Nowadays, with comprehensive studies that measure multiple -omics from the same sample, powerful tools for the integrative analysis of multi-omics datasets are required. RESULTS: Here, we present GeneTrail2, a web service allowing the integrated analysis of transcriptomic, miRNomic, genomic and proteomic datasets. It offers multiple statistical tests, a large number of predefined reference sets, as well as a comprehensive collection of biological categories and enables direct comparisons between the computed results. We used GeneTrail2 to explore pathogenic mechanisms of Wilms tumors. We not only succeeded in revealing signaling cascades that may contribute to the malignancy of blastemal subtype tumors but also identified potential biomarkers for nephroblastoma with adverse prognosis. The presented use-case demonstrates that GeneTrail2 is well equipped for the integrative analysis of comprehensive -omics data and may help to shed light on complex pathogenic mechanisms in cancer and other diseases. AVAILABILITY AND IMPLEMENTATION: GeneTrail2 can be freely accessed under https://genetrail2.bioinf.uni-sb.de CONTACT: : [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.