Ever since the discovery of depletion of CG sites in mammalian genomes it has been clear that cytosine DNA methyltransferases (DNMTs) are linked to the rate at which mutations accumulate in DNA. Research in the intervening decades has shown that DNMTs influence mutation rates through the indirect consequences of methylation on the mechanism of mutation and the mechanisms for DNA repair. Additionally, recent studies have shown that DNA methyltransferases have the potential to directly introduce damage into DNA. Here, I will discuss both aspects of the connection between DNMTs and DNA damage, evaluating the potential consequences for evolution across species and in human diseases such as cancer where cellular evolution plays a key role.