Allosteric modulators bound to structurally diverse allosteric sites can achieve better pharmacological advantages than orthosteric ligands. The discovery of allosteric modulators, however, has been traditionally serendipitous, owing to the complex nature of allosteric modulation. Recent advances in the understanding of allosteric regulatory mechanisms and remarkable availability of structural data of allosteric proteins and modulators, as well as their complexes, have greatly contributed to the development of various computational approaches to guide the structure-based discovery of allosteric modulators. This Perspective first outlines the evolution of the allosteric concept and describes the advantages and hurdles facing allosteric modulator discovery. The current available computational approaches, together with experimental approaches aiming to highlight allosteric studies, are then highlighted, emphasizing successful examples with their combined applications. We aimed to increase the awareness of the feasibility of the structure-based discovery of allosteric modulators using an integrated computational and experimental paradigm.