Several members of the Hsp70 protein family exist in the cytosol (bottom) of eukaryotic cells (yeast homologues are indicated in parentheses), whereas a single member, BiP resides in the ER (top). Three different classes of Hsp70 NEFs have been identified in the cytosol: large Hsp70 family members, Sil1-like and BAG-domain proteins that remove ADP from the NBD of Hsp70s, thus allowing ATP to bind and substrates to be released. A single member of the first and second class of NEFs, Grp170 and Sil1 respectively, have been found to act as nucleotide exchange factors for BiP in the ER. While Sil1-like and BAG-domain containing proteins are structurally unrelated to Hsp70 proteins, the large Hsp70 family of NEFs share many structural features with conventional Hsp70. The Hsp70 superfamily comprises conventional as well as large Hsp70s.