My presentation will mainly cover research from our group focused on somatic DNA alterations in the cancer genome. Chromothripsis scars the genome when localized chromosome shattering and repair occurs in a one-off catastrophe. Outcomes of this process are detectable as massive DNA rearrangements affecting one or a few chromosomes. While recent findings suggest a crucial role of chromothripsis in cancer development, the reproducible inference of this process has remained challenging, requiring that cataclysmic one-off rearrangements can be distinguished from localized genetic lesions that occur in a step-wise fashion. We have developed a set of conceptual criteria for the inference of complex DNA rearrangements suitable for rigorous statistical analyses, based on ruling out the alternative hypothesis that DNA rearrangements have occurred in a stepwise (progressive) fashion, and have recently devised an approach for characterization of chromothripsis events in vitro. Additionally, we have begun to perform analyses of deeply sequenced cancer genomes from 2,800 cancer patients in the context of the Pan Cancer Analysis of Whole Genomes (PWAG) project, to search for commonalities and differences in molecular processes leading to cancer in different disease entities. Our recent findings from the PCAWG dataset range from the identification of novel cancer predisposition loci to somatic rearrangements activating novel proto-oncogenes through ‘enhancer hijacking’.