Desymmetrization of prochiral cyclopentene‐1,3‐diones for the synthesis of various natural products and moieties of pharmaceutically active compounds, is a very challenging and competitive area of research in organic synthesis now a days. It is a very powerful strategy to provide quaternary stereocenter having different functionality, which is very difficult to install by other C−C bond‐forming methods. This review describes an elaborative discussion of desymmetrization of cyclopentene‐1,3‐diones (racemic and asymmetric) via different alkylation, arylation, amidation and cycloaddition process for the last decades.