A cell becomes cancerous when the genetic control systems that govern its division and death are disrupted in a manner that drives its uncontrolled proliferation. As that cell multiplies, its progeny accumulate DNA mutations and dramatic alterations to their programs of gene expression, driving the resulting tumor’s complexity. Ludwig researchers explore the cancer genome from a variety of angles to understand how such genomic dysfunction initiates cancer and then drives the evolution and metastasis of tumors. Their efforts include genome-wide analyses of how variations in DNA sequences influence the risk of cancer, how DNA repair mechanisms are disrupted in malignancies and how epigenetic marks—chemical modifications to DNA and its protein scaffolding that regulate gene expression—are redistributed across cancer genomes. These studies offer a more sophisticated view of cancer cell biology and are already contributing to the development of exciting new approaches to diagnose, treat and prevent cancers.