New details about the mechanism by which the APOBEC3 family of cytosine deaminases drive mutagenesis in human cancer cells are presented in this week's Nature. APOBEC3 has been implicated in some of the most prevalent mutational signatures in cancer, yet a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. To investigate mechanisms of APOBEC3 mutagenesis, a team led by researchers from the Broad Institute and Memorial Sloan Kettering deleted candidate APOBEC3 mutators from human cancer cell lines that generate the relevant mutations naturally over time. Analyzing non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder, and lymphoma cancer cell line clones reveals that deletion of the APOBEC3A enzyme diminished APOBEC3-associated mutational signatures. Other findings include the decrease, but not elimination, of APOBEC3 mutation burdens through the deletion of APOBEC3A and APOBEC3B. Overall, the findings represent "causal evidence for the hypothesis put forward two decades ago that APOBEC3 enzymes can act as endogenous sources of mutation in cancer.