In the cell, proteins interact within a network in which a small number of proteins are highly connected nodes or hubs. A disturbance in the hub proteins usually has a higher impact on the cell physiology than a disturbance in poorly connected nodes. In eukaryotes, the cytosolic Hsp90 is considered to be a hub protein as it interacts with molecular chaperones and co-chaperones, and has key regulatory proteins as clients, such as transcriptional factors, protein kinases and hormone receptors. The large number of Hsp90 partners suggests that Hsp90 is involved in very important functions, such as signaling, proteostasis and epigenetics. Some of these functions are dysregulated in cancer, making Hsp90 a potential target for therapeutics. The number of Hsp90 interactors appears to be so large that a precise answer to the question of how many proteins interact with this chaperone has no definitive answer yet, not even if the question refers to specific Hsp90s as one of the human cytosolic forms. Here we review the major chaperones and co-chaperones that interact with cytosolic Hsp90s, highlighting the latest findings regarding client proteins and the role that posttranslational modifications have on the function and interactions of these molecular chaperones. This article is part of a Special Issue entitled: Proteomics: The clinical link.752790-802