Accumulated damage to DNA (i.e., mutation) is a driving force behind evolution, and the rate at which this damage accumulates can help to set the pace of evolution. If this rate of damage can be quantified, then the damage itself can be used to determine the time at which species last shared a common ancestor. DNA damage is also associated with aging and disease in multi-cellular organisms. Many factors, each affecting DNA differently, are present in the environment, and each of these has changed over the history of life on Earth. In addition, the dominant DNA-damaging agent(s) vary through time and according to an organism’s lifestyle. These facts suggest that determining the mutagenic history of an organism or lineage is not a simple matter. We find that calculated rates of DNA damage today vary by more than an order or magnitude depending on the exposure of an organism to UV light, oxygen, and mitochondria. The latter two agents are most important to modern life. We further find that, in the past, the “mix” of DNA-damaging agents was different than today with UV light and ionizing radiation being the primary mutagens. In addition, overall rates of DNA damage in the distant past were much higher than they are today for most organisms. This information suggests that knowledge of an organism’s lifestyle and the time at which it lived are primary factors controlling rates of genetic change, and that organisms have experienced different rates of mutation at various times in the past. In addition to having implications for molecular clock dating of divergence times in the deep geologic past, we suggest that the manner in which modern organisms respond to DNA damage may reflect the mutagenic environment in which that organism’s lineage evolved.