Xylene isomers, including para-xylene (pX), meta-xylene (mX), ortho-xylene (oX), and ethyl benzene (EB), are important raw materials in industry. The separation of xylene isomers has been recognized as one of the "seven chemical separations to change the world". However, because of their similar physicochemical properties, totally separating four xylene isomers has remained a big challenge until now. Metal-organic frameworks (MOFs) have emerged as promising separators to achieve this goal because MOFs synergistically provide multiple mechanisms at the molecular scale. In this review, we summarize the recent progress of MOFs as separators for the separation of xylenes based on four main separation mechanisms: the molecular sieving effect, gating mechanism, thermodynamic interactions, and kinetic diffusion. We concentrate on the applications of MOFs in the field of chromatography, single-component vapor adsorption, liquid-phase competitive adsorption, breakthrough, and membrane separation. Finally, we conclude with the possible direction for designing high-performance MOF separators and briefly discuss the existing challenges in this area.