To maintain genome stability, the cell has to limit initiation of DNA replication to once per cell cycle. Loss of this control leads to DNA rereplication with repeated firing of replication origins in the same cell cycle. Rereplication generates both ssDNA and double strand breaks, as well as activation of the DNA damage checkpoint. In rereplicated cells, activation of the checkpoint is critical to arrest cells in G2 resulting in accumulation of cells with rereplicated DNA. Abrogation of this checkpoint suppresses the progressive accumulation of cells with excess DNA and causes apoptosis. Recently, the Fanconi Anemia pathway was reported to be activated in rereplicating cells. Interestingly, FA core complexes but not FANCD2, is required for checkpoint activation in rereplicated cells, suggesting that the pathway to checkpoint activation requires the ubiquitination of substrates other than FANCD2. In addition, FANCD2 is required for recruitment of Rad51 to foci in rereplicated cells, so that the repair pathways activated after small degrees of rereplication are expected to be compromised in cells with mutations in the FA pathway. ©2006 Landes Bioscience.