Repetitive DNA motifs may fold into non-B DNA structures, including cruciforms/hairpins, triplexes, slipped conformations, quadruplexes, and left-handed Z-DNA, thereby representing chromosomal targets for DNA repair, recombination, and aberrant DNA synthesis leading to repeat expansion or genomic rearrangements associated with neurodegenerative and genomic disorders. Hairpins and quadruplexes also determined the relative abundances of simple sequence repeats (SSR) in vertebrate genomes, whereas strong base stacking has permitted the expansion of purine·pyrimidine-rich SSR during evolutionary time. SSR are enriched in regulatory and cancer-related gene classes, where they have been actively recruited to participate in both gene and protein functions. SSR polymorphic alleles in the population are associated with cancer susceptibility, including within genes that appear to share regulatory circuits involving reactive oxygen species. © 2009 Wiley-Liss, Inc.