Mutations in DNA sequence and inherited genetic disease are two fundamental concepts in the field of human genetics. There is debate over whether disease-associated mutations are caused by extrinsic factors, such as environmental exposures, or intrinsic factors like replication errors and cellular respiration, leading to spontaneous mutations. In this issue, Cooper et al. (Hum Mutat 32:1075–1099, 2011) have reviewed the existing literature and shown that the occurrence of any mutation, starting from subtle point mutations to gross genomic rearrangements, is a function of features of the inherent genetic sequence including base composition, sequence repetition and/or epigenetic modification.

This review is co-authored by six individuals who have made major contributions to the understanding of sequence-directed mechanisms underlying human mutations over the last two decades. It is a comprehensive review of the sequence context of all known mutation types. The authors start with mutations in CpG islands, which are highly predictable, and move on to document mutations in CpNpG tri-nucleotide sequences. Methylation-mediated deamination of 5mC in the latter group is also responsible for the mutations. Moving on from point mutations, the authors further strengthen their case by discussing multiple examples of micro-deletions and insertions that are similar to sequence motifs present in the flanking regions including repeat sequences. Next they provide extensive documentation in support of the role of non-canonical DNA structures in large genomic rearrangements. In the end, the evidence is clearly summarized to support the role of intrinsic DNA sequence and the associated non-B DNA structural elements as predictable determinants of specific mutations.