In recent years, intrinsically disordered proteins (IDPs) have attracted a lot of attention given the functional importance inherent to their flexible nature. One of the most intriguing features of IDPs is their ability to undergo disorder-to-order transitions upon binding in order to perform their function. Although the importance of intermolecular interactions involving IDPs has been widely recognized, there are divergent views on their binding mechanisms. Among the existing mechanistic models, two of them have gained popularity in the IDP field: the 'conformational selection' and the 'coupled folding and binding.' The first mechanism suggests that folding of IDPs precedes binding, while the second mechanism argues that folding may only take place upon binding. It has been suggested that both models are valid, although they work independently. However, reinterpretation of recent experimental and theoretical data indicates that both models have much more in common that it has been thought. In this manuscript, it is proposed that both mechanistic models should be merged into a single one: the synergistic model. In this model, both 'conformational selection' and 'coupled folding and binding' will synergistically participate in the binding of IDPs. To what extent each model will contribute to the full binding mechanism will depend on the required rate of binding, IDPs concentration, the native local plasticity of IDPs, the degree of binding degeneracy and the type of disorder-to-order transition. Furthermore, it is proposed that combination of the two mechanisms would bring tremendous advantages to IDP binding. For example, synergy may effectively modulate binding kinetics, balance the delicate interplay between enthalpy and entropy by using the funneled energy landscape more efficiently, thus yielding high specificity with carefully balanced free energy of binding. Given the advantages of the synergistic model, it is proposed that it will provide the basis to fully understand the complex nature of IDP binding. (C) 2009 Elsevier Inc. All rights reserved.