Recent years have witnessed tremendous progress in our structural and biophysical understanding of how replication protein A (RPA), a major nuclear ssDNA-binding protein (SSB), binds DNA. The four ssDNA-binding domains of RPA have the characteristic OB (oligonucleotide/oligosaccharide-binding) fold and contact DNA with specific polarity via a hierarchy-driven dynamic pathway. A growing mass of data suggest that many aspects of the ssDNA binding mechanism are conserved among SSBs of different origin. However, this conservation is not restricted to the SSB class. The concepts of ssDNA binding by the OB-fold, first derived from the RPA structure, have been successfully applied to the functional characterization of the BRCA2 (breast cancer susceptibility gene 2) protein. The BRCA2 structure, in its turn, has helped to better understand RPA function.