The separation of C2H2 and CO2 is of industrial significance but is highly challenging due to their close similarities in physical-chemical properties. Metal-organic frameworks (MOFs) with tailored pore structures and tunable pore surfaces for the separation of C2H2/CO2 mixture are described in this perspective article. In terms of adsorption selectivity, MOF is classified into C2H2-selective MOF and CO2-selective MOF, which are discussed separately. Herein, we intend to present a short summary of the important advancements in C2H2/CO2 separation with MOFs. The relationship between the separation performance and structural features of MOFs, together with the separation mechanisms, has been discussed in detail. The challenges, research trends and opportunities in C2H2/CO2 separation with MOFs are highlighted.