A defect of DNA repair is the factor underlying the chromosome instability syndromes, also known as chromosome breakage syndromes. The “instability” refers to the predisposition of the chromosomes to undergo rearrangement or to display other abnormal cytogenetic behavior. The classic chromosome instability syndromes are individually rare: Fanconi syndrome, ataxia-telangiectasia, and Bloom syndrome. Smaller-print conditions are yet more rare, including Roberts syndrome; the immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome; and Nijmegen breakage syndrome. The role of cytogenetics in diagnosis is less central than formerly, but the interest in these conditions remains, and this chapter provides a full listing. Autosomal recessive inheritance is typical, albeit not universal.