Continuous improvements in our understanding of molecular carcinogenesis, in particular the detailed characterization of cancer-driving mutations and aberrantly activated intracellular signaling pathways, which are critically involved in cancer development and progression, has led to the identification of new potential targets for diagnostic and therapeutic intervention. Thus far, however, only a few molecular markers, such as mutant RAS in colorectal cancer, activating BRAF mutations in melanoma or alterations of the KIT and PDGFRA genes in gastrointestinal stromal tumors, are established in the clinical setting, and most treatment decisions in oncology remain exclusively based on histomorphologic diagnoses. Several studies have highlighted that comprehensive molecular analyses of individual tumors using modern genome sequencing technology can be highly informative regarding the underlying biology and may therefore provide opportunities for molecularly targeted, personalized treatment approaches. However, the integration of comprehensive genomic analyses into clinical routine remains a formidable challenge. The MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program at NCT Heidelberg, a molecularly stratified registry trial, addresses this problem and provides comprehensive molecular diagnostics in a clinical setting to identify entry points for tailored therapeutic intervention in younger patients with advanced-stage cancers. Based on a standardized workflow and an established infrastructure, the program aims to offer clinical cancer genome sequencing to adult patients with advanced-stage malignancies and to systematically evaluate the efficacy of molecularly stratified therapeutic interventions.