The design of high-affinity and analyte-selective receptors operating in aqueous solutions is an outstanding problem in supramolecular chemistry. Directing the focus toward the unique properties of water, we present here a new strategy toward this goal and support it by molecular dynamics simulations and calorimetric measurements. We illustrate the procedure in the case of self-assembled 1:1 complexes of the rigid macrocycle cucurbit[8]uril (CB8) and dicationic auxiliary guests (AG). These CB8 center dot AG complexes contain residual water molecules whose conformational space and hydrogen-bond formation ability is restricted by the geometrically confined and hydrophobic cavity of the receptor. We show that upon inclusion of an analyte to form a 1:1:1 CB8 center dot AG center dot analyte complex, these high-energy cavity water molecules are released to the aqueous bulk, providing a strong enthalpic driving force to the association, and resulting in binding constants of up to 10(6) M-1 for aromatic analytes. This binding model is supported by the measurements of large solvent and solvent isotope effects. The selectivity of the CB8 center dot AG receptor can be modified or even switched toward small aliphatic analytes by a rational choice of the auxiliary guest, demonstrating the tunable recognition features of such self-assembled receptors. Furthermore, by comparison of the results to those for the extensively studied macrocyclic host cyclobis(paraquat-p-phenylene)the so-called blue-boxit is shown that in aqueous solution the release of high-energy water molecules from the CB8 center dot AG cavity can be more favorable than the use of direct hostguest interactions