The Hsp90 molecular chaperone is composed of four family members that play key roles in the folding of nascent polypeptides as well as the rematuration of misfolded proteins. The cytostolic chaperones, Hsp90a and Hspd0b, contribute to tumorogenesis and represent attractive targets for the treatment of cancer. Grp94 is the ER-localized paralog that is responsible for the trafficking of proteins, such as myocillin, and consequently represents an ideal target for the treatment of primary open angle glaucoma. In contrast to the inhibition of Hsp90, the molecular chaperones can be overexpressed to exhibit neuroprotective activity in animal models of neuropathy. While the Hspg0 isoforms play key roles in various diseases, the N-terminal ATP-binding site is >85% identical, making the development of selective inhibitors challenging. In this presentation, methods used to develop isoform-selective inhibitors will be disclosed as well as some of the early preclinical studies that are being pursued for translation.