The last three decades has seen a revolution in our ability to characterize cancer genomes and apply this knowledge to clinical questions. In oncology, these applications began with inherited predispositions to cancer and progressed to applications of somatic cancer genomes. Recent technological advances now allow the sensitive detection of trace levels of altered genomes and introduced the era of mutations as biomarkers (e.g. liquid biopsies). This lecture will briefly review the progression of clinical applications and then focus on the utility of trace genomes for the earlier detection of cancer.