Fanconi anemia (FA) is a chromosome instability syndrome characterized by progressive bone marrow failure and cancer proneness. The proteins mutated in FA constitute the so-called FANC/BRCA pathway, involved in DNA replication and damage response. However, it is not completely understood how the FANC proteins perform their functions and maintain chromosome stability. Two recently published works reported that FANCD2 localizes to discrete sites on mitotic chromosomes, as consequence of replication fork stalling. The FANC pathway proved to be required to promote BLM-mediated anaphase resolution of chromosome entanglements induced by replication stress. It has also been shown that chromosome entanglement derives from DNA intertwining at fragile sites and that FANCD2 specifically targets these sites. Collectively, our data highlight a new role for the FANC proteins in the prevention of chromosome instability and aneuploidy. These findings open new directions in understanding the mechanisms of chromosome fragility and the role of FANC proteins in preserving genome stability.