Here I discuss findings that suggest a universal mechanism for proteins (and RNA) to recognize and interact with various binding partners by selectively binding to different conformations that pre‐exist in the free protein's conformational ensemble. The tandem RNA recognition motif domains of splicing factor U2AF65 fluctuate in solution between a predominately closed conformation in which the RNA binding site of one of the domains is blocked, and a lowly populated open conformation in which both RNA binding pockets are accessible. RNA (...) binding to U2AF65 may thus occur through the weakly populated open conformation, and the binding interaction stabilizes the open conformation. The conformational diversity observed in U2AF65 might also facilitate binding to diverse RNA sequences as found in the polypyrimidine tracts that help define 3′ splice sites. Similar binding pathways in other systems have important consequences in biological regulation, molecular evolution, and information storage. (shrink)