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The exonuclease and endonuclease activities of the DNA polymerases, which extend their proof-reading capabilities and maintain high fidelity in the replication process, apparently conflict with the principle of microscopic reversibility. However, in-depth mechanistic analysis of the reactions leads to fascinating insights into the kinetic and thermodynamic effects controlling the replication of the primary genetic material. Thus, nucleotide addition and excision involve different pathways, although a violation of microscopic reversibility is avoided as the overall reaction does not reach equilibrium. Intriguingly, however, this allows the fidelity levels to exceed those expected from simple kinetic control.