DNA/RNA-editing enzymes are highly divergent amongst species, in particular between land and sea dwellers. We believe a strong reason for this fascinating divergence is co-evolution with their role in immunity and the race against the unique pathogens that each species faces in its environment. Only partial or no DNA-editing enzymes have been identified in many evolutionary distant species, and this is an understudied area relative to human enzymes. We have been conducting comparative biochemical and structure:function studies of distantly-evolved DNA-damaging enzymes. We have discovered several novel enzymes, found that many fish AID/APOBECs have many different biochemical properties, fascinatingly divergent from other enzymes, and we have found that these molecular properties can allow the enzymes to carry out diverse non-immune biological roles. Our previous works in this area have demonstrated the value of this evolutionary comparative approach in gaining insights into mechanisms and structures of human DNA damaging enzymes and in tackling several biological dogmas. Discovering and characterizing distantly evolved orthologs and ancestors of AID/APOBECs and other ancient DNA damaging enzymes is providing novel insights into evolution and biology, while in parallel generating new research tools towards mechanistic and structure:function insights in our human health-related research areas.