The concept of preorganization suggests that organizing a receptor around its guest during binding is detrimental, because the cost of conformational change is assumed to be paid out of the binding energy. Although this concept has historically guided the synthesis of a great many synthetic hosts, in recent years, chemists have begun to synthesize receptors that resemble proteins in their cooperative conformational changes. Such changes could enhance the host–guest interactions, in particular if the binding of the guest triggers previously unengaged noncovalent interactions within the host. These hosts, referred to as cooperatively enhanced receptors, corroborate with their biological counterparts to support the approach of creating high-affinity receptors through the combined strategies of cooperativity and preorganization. Solvents, often the invisible participants of any solution-based supramolecular process, should be properly considered in the design of synthetic receptors, whether preorganized or cooperatively enhanced.