Fragile sites are the cytogenetic manifestation of a peculiar genome structure. Two fundamentally different types occur: rare fragile sites that are characterized by repeat expansion and common fragile sites that consist of AT-rich regions which may stretch over megabases and that are prone to chromosomal rearrangements. In contrast to common fragile sites that are presumably present in all individuals, rare fragile sites are found in maximally 5% of the population. A relationship between the rare fragile site at Xq27.3 and fragile X syndrome, the most common form of inherited mental retardation has been well established. In addition, causative genomic rearrangements within the two most frequently observed common fragile sites in specific tumours were demonstrated. Currently, more than 100 different fragile sites have been described and a potential role for additional fragile sites in human disease, including intellectual disability, autism, neurodegeneration, cancer and chromosome truncation syndromes, is emerging. We use rare fragile sites to clone novel dynamic mutations and investigate their role in disease.