PCNA (proliferating cell nuclear antigen), originally characterized as a DNA polymerase accessory protein, functions as a DNA sliding clamp for DNA polymerase delta and is an essential component for eukaryotic chromosomal DNA replication. Recent studies have revealed a striking feature of PCNA in its ability to interact with multiple partners, involved, for example, in Okazaki fragment joining, DNA repair, DNA methylation and chromatin assembly. Since these reactions take place mainly on replicating DNA, PCNA has applications as a marker for DNA synthesis. It is of interest that proteins involved in cell cycle regulation may also exhibit PCNA binding activity. For example, the CDK inhibitor, p21 (Cip1/Waf1) interacts with PCNA blocking its activity necessary for DNA replication and also affecting interactions with other PCNA binding proteins. The available data indicate that DNA sliding clamps have generated additional functions with evolution of eukaryotes from simple prokaryotes. In mammalian cells, they play key roles in controlling DNA synthesis reactions and the reorganization of replicated DNA at replication forks. Several cell cycle regulation proteins target these processes by affecting PCNA actions.