Genomic rearrangements may give rise to congenital disease and contribute to cancer development. Recent evidence has shown that very complex genomic rearrangements in cancer cells can result from a single catastrophic event of massive DNA breakage and repair, termed chromothripsis. This results in heavily rearranged chromosomes comprising frequent sequence losses. A very similar process of chromosome shattering is found for complex chromosome rearrangements in the germline of patients with congenital disorders. Here, we review the literature on chromothripsis in cancer and congenital disease. We describe differences and similarities for chromothripsis rearrangements in somatic tissue and the germ line and we discuss the cellular origin and molecular mechanisms of chromothripsis.