Cancer is the second highest cause of death in the United States. A greater understanding of the underlying causes of this disease is critical to improve patient outcomes. For years, researchers have known that cancer is primarily a genetic disease, caused by mutations that can activate oncogenes and inactivate tumor suppressors. Several studies have also shown that UV radiation, smoking and certain defects in DNA repair cause some of the mutations that lead to cancer, but the sources of mutations found in many tumor types are yet to be explained. Here, we build upon our initial finding that APOBEC3B is a source of mutation in breast cancer by defining its role in ovarian cancer. Parallel analyses looking globally at mutation in cancer have shown that APOBEC3B also contributes to mutation in several other tumor types. Additional studies have elucidated a major signaling mechanism that regulates APOBEC3B expression in cancer. While many efforts have been made to directly inhibit APOBEC3B enzymatic activity, the advances described here have the potential to inform alternative therapeutic strategies aimed at transcriptionally downregulating APOBEC3B to slow tumor evolution and improve the durability of conventional anti-cancer drugs. Ultimately, a more comprehensive understanding of the basic biology of APOBEC3B catalyzed mutagenesis in cancer will translate to larger impacts in the clinical arena.