The widely-expressed molecular chaperone heat shock protein 90 (Hsp90) regulates several important cellular processes via its' repertoire of 'client' proteins. Signal transduction pathways controlled by Hsp90 contribute to all major components of the malignant phenotype, so Hsp90 inhibitors are under investigation as anticancer agents. Since Hsp90 is also expressed at high levels in many normal tissues, it was unclear why Hsp90 inhibitors such as 17-allylamino-geldanamycin (17-AAG) have selective antitumor activity in animals and are well tolerated clinically. Recent findings indicate that Hsp90 is largely latent in unstressed normal cells, but tumor Hsp90 becomes completely utilized during malignant progression, resulting in an activation-dependent conformational shift that radically increases 17-AAG binding affinity in cancer cells. In this article, the implications of this discovery are discussed, with particular reference to cell cycle regulation in normal and malignant cells, and the consequences of inducing cell cycle arrest with Hsp90 inhibitors.