An increased mutation rate in human cells is a critical contributing factor for the development of malignancy. Many autosomal recessive genetic disorders are known, in which an increased mutation rate and predisposition for cancer can be attributed to a deficiency in DNA repair or associated processes. Some of these DNA repair deficiencies are manifested at the level of the mitotic chromosome as increased breakage, particularly after treatment with specific mutagens. The examination of the response of cells from patients with these disorders to carcinogens offers the opportunity to elucidate the mechanisms operating in human cells to combat DNA damage and mutation. Over the last few years, the underlying genes in many of these syndromes have been identified, enabling a much more detailed definition of the processes disturbed. This review concentrates on two of the chromosomal breakage syndromes, Fanconi anaemia and Nijmegen breakage syndrome, which have both distinct and common cellular features.