Abstract: Coordinated replication of eukaryotic nuclear genomes is asymmetric, with copying of a leading strand template preceding discontinuous copying of the lagging strand template. Replication is catalyzed by DNA polymerases alpha, delta and varepsilon, enzymes that are related yet differ in physical and biochemical properties, including fidelity. Recent studies suggest that Pol varepsilon is normally the primary leading strand replicase, whereas most synthesis by Pol delta occurs during lagging strand replication. New studies show that replication asymmetry can generate strand-specific genome instability resulting from biased deoxynucleotide pools and unrepaired ribonucleotides incorporated into DNA during replication, and that the eukaryotic replication machinery has evolved to most efficiently correct those replication errors that are made at the highest rates.CI - Published by Elsevier Ltd.