The development, survival, and reproduction of an organism depend on the genetic information that is carried in its genome, yet the transmission of genetic information is not perfectly accurate: new mutations occur at each generation. These mutations are the primary cause of the genetic diversity on which natural selection can operate, and hence are the sine qua non of evolution. A better knowledge of mutation processes is crucial for investigating the causes of genetic diseases or cancer and for understanding evolutionary processes. This knowledge is also important for different practical reasons. First, comparative sequence analysis is widely used to find functional elements within genomes. The basic principle of this approach is that functional elements are affected by natural selection, and hence can be recognized because they evolve either slower or faster than expected given the local mutation rate. Hence, to be able to annotate genomic sequences, it is necessary to have a good knowledge of the underlying pattern of mutation. Moreover, this knowledge is also essential for ensuring the accuracy of the methods that analyze sequence divergence to determine the phylogeny of species or the demographical history of populations. Finally, the study of mutational processes also provides valuable information about genome function in processes such as replication, repair, transcription, and recombination. During the last few years, several important factors affecting mutation rates have been uncovered. However, a paper in this issue of PLoS Biology [1] reveals an unexpected additional layer of complexity in the determinants of mutation rates.