DNA topology changes dynamically during DNA replication. Supercoiling, precatenation, catenation and knotting interplay throughout the process that is finely regulated by DNA topoisomerases. In the present article, we provide an overview of theoretical and experimental approaches to understand the interplay between various manifestations of topological constraints acting on replicating DNA molecules. Data discussed reveal that DNA entanglements (supercoils and catenanes) play an active role in preventing the formation of deleterious knots.