The availability of drugs that can specifically target Hsp90 and inhibit its function, resulting in the depletion of client proteins, has made Hsp90 a novel and exciting target for cancer therapy. The current HSP90 inhibitors are developed from geldanamycin and radicicol which are the natural product inhibitors and are starting point for new approach. HSP 90 is required for ATP dependent refolding of denatured or unfolded proteins and for the conformational maturation of a subset of proteins involved in the response of cells to extracellular signals. These include steroid receptors Raf – 1, Akt, Met and Her 2. HSP90 has conserved unique pocket in N terminal region. It binds ATP & ADP and has weak ATPase activity. This suggests that site acts as nucleotide or nucleotide ratio sensor. It is observed that nucleotides adopt unique C shaped bent shape when binding to this pocket. This is particularly unusual as nucleotides never adopt shape change in high affinity ATP/ADP sites. This also indicates that drugs that are developed should also have potential to adopt unique C shape conformation in order to bind the unique pocket. The rationale for this unusual need i.e. to bend the structure, is based on thermo dynamical fact that the molecule which needs minimum structural changes to go from unbound to bound state should not pay much entropic penalties and binding would be reflected by enthalpic factors. Geldanamycin and radicicol tightly bind to this pocket and prevent the release of protein from chaperone complex. Thus the protein cannot achieve native conformation and is degraded by proteosome. Addition of such inhibitor causes proteosomal degradation of signaling proteins like steroid receptors, Raf kinase and Akt. Geldanamycin and radicicol also inhibit mutated protein in cancer cells like P53, Vsrc, BCR – ABL. It is worth to note that the normal counterparts are not inhibited. Geldanamycin is an effective HSP90 inhibitor still it cannot be used in vivo because of its high toxicity and liver damage ability. The speculation is that the benzoquinone functional group is responsible. The semi-synthetic derivative 17 AAG, with lower toxicity but same potency as geldanamycin is developed and is currently under clinical trials.  17-N-Allylamino-17-demethoxygeldanamycin (17AAG) is the semi-synthetic derivative of natural product Geldanamycin.