The ninety kilo Dalton molecular weight heat shock protein (Hsp90) is an attractive target for the discovery of novel anticancer agents. Several strategies have been employed for the development of inhibitors against this polypeptide. The most successful strategy is targeting the N-terminal ATP binding region of the chaperone. However, till date not a single molecule reached Phase-IV of clinical trials from this class of Hsp90 inhibitors. The other approach is to target the Cterminal region of the protein. The success with this approach has been limited due to lack of well-defined ligand binding pocket in this terminal. The other promising strategy is to prevent the interaction of client proteins/co-chaperones with Hsp90 protein, i.e., protein-protein interaction inhibitors of Hsp90. The review focuses on advantage of this approach along with the recent advances in the discovery of inhibitors by following this strategy. Additionally, the biology of the client protein/co-chaperone binding site of Hsp90 is also discussed.