The autosomal recessive disease Fanconi anemia (FA) causes bone marrow failure and a hugely increased propensity to develop cancer. Cells from FA patients are prone to chromosome breakage, indicating that FA gene products are required to ensure genomic integrity. Most of the identified FA proteins are components of a nuclear complex whose principal function is to activate FANCD2 by monoubiquitination. Monoubiquitinated FANCD2 accumulates at sites of genome damage, where it probably functions to facilitate DNA repair. A recent paper in Molecular Cell (Nijmanet al., 2005) reports the identification of an enzyme that is responsible for regulating the FA pathway by deactivating FANCD2.