Tumorigenesis involves different layers of deregulation. Genomic alterations accumulate during cell divisions due to different mutational  processes, and those providing a growth advantage promote the clonal expansion of tumor cells. The epigenetic and transcriptomic programs are also remodeled, allowing plasticity between more or less aggressive cell states. Here I will show how the integration of various types of omics data can unravel new oncogenic mechanisms and reveal the natural history of cancers, from tumor initiation to treatment resistance. I will also discuss how AI can help making sense of genomic data.