Overview depicting the relationship between APOBEC3-mediated mutagenesis [X-axis] and tumor fitness [Y-axis] as a function of suitable anti-cancer treatments. Standard-of-care therapies, such as tamoxifen and radiotherapy, are suitable when APOBEC3 activity is low, driving down tumor fitness. On the other hand, immune checkpoint inhibition, synergistic drugs [such as DNA intercalating agents], and synthetically lethal combinations [such as ATRi] can exploit the weaknesses brought about by APOBEC3-mediated mutagenesis. Inhibitors of A3A and/or A3B, currently in development, may also be used to limit APOBEC3-mediated genomic diversification and sensitize to other treatments.