APOBEC3A hairpin passenger hotspots Genomic features are often examined at extremes to determine the impact of mutations. These genomic regions span from the trinucleotide context to megabases that underlie chromatin and chromosomal features. Examining mutational dynamics at the mesoscale, the intermediate span of the genome, Buisson et al. characterized the mutational dynamics of cancer (see the Perspective by Carter). They found that mutations caused by the APOBEC enzyme in DNA stem-loops, a mesoscale feature of the genome, could drive recurrent mutations. Many of these types of mutations have been identified as likely drivers of cancer. However, APOBEC-generated mutations outside of stem-loops were more likely to be cancer driver mutations, providing a genomic context for separating cancer driver from passenger mutations. Science , this issue p. eaaw2872 ; see also p. 1228