This chapter describes the fundamental ideas that led to the discovery of the purine-based Hsp90 inhibitors BIIB021 and BIIB028. The first-generation drug BIIB021 completely inhibits tumor growth in murine cancer models when administered orally at its maximum tolerated dose (MTD, 625 mg/kg/week, p.o.). BIIB021 is the first Hsp90 inhibitor to have entered clinical trials as an oral drug, and completed Phase II clinical trials. The second-generation compound, BIIB028, is a highly water-soluble molecule designed for parenteral administration. BIIB028 is a phosphate pro-drug that releases the active metabolite CF2772 in vivo. In mouse models, BIIB028 has an unprecedented efficacy and tolerability. It causes tumor regressions at its maximum tolerated dose (MTD, 120 mg/kg/week, i.v. or i.p.) and still prevents tumor growth when given at only one-eighth of its MTD; this makes BIIB028 a potentially best-in-class drug. BIIB028 completed Phase I studies as an intravenous formulation.