Conformational plasticity of the Hsp90 molecular chaperones underlies the diversity of functional mechanisms that these versatile molecular machines employ to coordinate their vast protein clientele in the cellular environment. Despite a steady progress in studies of the Hsp90 machinery, a great deal remains unknown about molecular principles and ligand-specific functional mechanisms of the Hsp90 regulation by allosteric modulators that attracted significant attention because of their therapeutic potential. Due to structural complexity and dynamic nature of the Hsp90 responses to allosteric modulators, the atomistic details about the mode of action of these small molecules continue to be fairly scarce and controversial. In this work, we employ an integrative strategy that encompassed atomistic simulations of the Hsp90 proteins and hierarchical modeling of Hsp90-ligand binding with network analysis to explore functional mechanisms of the Hsp90 regulation by a panel of allosteric modulators (novobiocin, KU-135, KU-174, and KU-32) with different models of action. The results show that functional mechanisms of allosteric modulation in the Hsp90 proteins may be driven by conformational selection principles in which ligands elicit pre-existing states of the unbound chaperone to drive ligand-specific protein responses and distinct scenarios of Hsp90 regulation. We found that novobiocin can selectively sequester an ensemble of open chaperone conformations and inhibit the progression of the functional cycle through a cascade of cumulative dynamic changes. In contrast, KU-32 displayed unique preferences toward partially closed dynamic states, inducing robust allosteric signaling and stimulation of the ATPase cycle. The proposed model of the Hsp90 regulation by allosteric modulators reconciled diverse experimental data and showed that allosteric modulators may operate via targeted exploitation of dynamic landscapes eliciting vastly different protein responses and diverse mechanisms of action.