Genotype-to-phenotype mapping commonly focuses on two major classes of mutations: single nucleotide polymorphisms (SNPs) and copy number variation (CNV). Here, we discuss an underestimated third class of genotypic variation: changes in microsatellite and minisatellite repeats. Such tandem repeats (TRs) are ubiquitous, unstable genomic elements that have historically been designated as nonfunctional "junk DNA" and are therefore mostly ignored in comparative genomics. However, as many as 10% to 20% of eukaryotic genes and promoters contain an unstable repeat tract. Mutations in these repeats often have fascinating phenotypic consequences. For example, changes in unstable repeats located in or near human genes can lead to neurodegenerative diseases such as Huntington disease. Apart from their role in disease, variable repeats also confer useful phenotypic variability, including cell surface variability, plasticity in skeletal morphology, and tuning of the circadian rhythm. As such, TRs combine characteristics of genetic and epigenetic changes that may facilitate organismal evolvability.