During every cell cycle, the entire genome must be duplicated just once to preserve genome integrity. Over-replication is prevented by multiple mechanisms that block the premature reformation of the pre-replicative complex(pre-RC) at replication origins. Regulation of Cdt1 activity, a pre-RC component, is especially important in inhibiting re-replication. Calvi and colleagues now report that overexpression of Double-parked (Dup), the Drosophila orthologue of Cdt1, is sufficient to induce re-replication during development, resulting in polyploidy and cell death in the ovary and imaginal discs (see p. 4807). The researchers show that the phosphorylation and degradation of Dup at G1/S,which prevents re-replication, is dependent on cyclin E/CDK2 activity. Finally, by showing that Dup activity is regulated differently during genomic replication than during the developmental amplification of genes in follicle cells late in oogenesis, the researchers provide important insights into the mechanism of gene amplification, a developmentally specific replication programme.