Human Proliferating Cellular Nuclear Antigen (hPCNA), a member of the sliding clamp family of proteins, makes specific protein-protein interactions with DNA replication and repair proteins through a small peptide motif termed the PCNA-interacting protein, or PIP-box. We solved the structure of hPCNA bound to PIP-box-containing peptides from the p66 subunit of the human replicative DNA polymerase-δ (452–466) at 2.6 Å and of the flap endonuclease (FEN1) (331–350) at 1.85 Å resolution. Both structures demonstrate that the pol-δ p66 and FEN1 peptides interact with hPCNA at the same site shown to bind the cdk-inhibitor p21^CIP1. Binding studies indicate that peptides from the p66 subunit of the pol-δ holoenzyme and FEN1 bind hPCNA from 189- to 725-fold less tightly than those of p21. Thus, the PIP-box and flanking regions provide a small docking peptide whose affinities can be readily adjusted in accord with biological necessity to mediate the binding of DNA replication and repair proteins to hPCNA.