The Fanconi Anemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks, and responds to replication stress. Genetic inactivation of this pathway impairs development, results in bone marrow failure and promotes cancer. The key molecular step in the FA pathway is the monoubiquitination of FANCD2-FANCI by the FA core complex-a megadalton multiprotein E3 ubiquitin ligase. Monoubiquitinated FANCD2 is thought to recruit enzymes to remove the DNA cross link or to stabilize the stalled replication fork. We recently reconstituted an active, recombinant FA core complex that efficiently monoubiquitinates FANCD2-FANCI in vitro and used electron cryo-microscopy (cryoEM) alongside mass spectrometry to determine the structures of several complexes. I will describe our efforts to understand how the proteins in the FA pathway signal and repair DNA crosslinks.