Heat shock protein 90 (Hsp90) is a highly efficient molecular chaperone and a major hub in the protein network that maintains cellular homeostasis and function. The qualitative and quantitative changes and rewiring of this protein network in tumor cells make them vastly dependent on Hsp90, which therefore becomes a key target to fight cancer. The inhibition of Hsp90 creates a profound transformation in the cell proteome. In this chapter, we review and analyze the most recent efforts that take advantage of the druggability of Hsp90 in order to understand the global changes at the proteome level that this inhibition produces. The considerable impact that the targeting of Hsp90 has on the structure of these protein networks is also discussed.