The performance of many emerging multinary chalcogenides for photovoltaic (PV) applications has been considerably inferior to the Shockley–Queisser limit, and one of the main reasons for this is the existence of various detrimental deep-level defects and defect clusters. Among them, the development of kesterite-based Cu₂ZnSn(S_x,Se_1−x)₄ (CZTCh) solar cells is currently hindered by a large open-circuit voltage deficit (V_oc,def). Much of this V_oc,def could be ascribed to the abundant cation disorder and defect clusters in the CZTSSe absorber layer, which is the origin of band-tail states caused by electrostatic potential fluctuations. To deal with the above intractable issues encountered in kesterite-like materials, a partial or complete cation substitution strategy offers a viable pathway to alter the characteristics of such deleterious defects and defects clusters, namely, (i) partial cation substitution can introduce ionic-size mismatch for alleviating antisite disorder and/or detrimental defect clusters to mitigate a large V_oc,def and (ii) complete cation substitution can be expected to eliminate notorious band-tail states. This can foster the development/exploration of many emerging multinary chalcogenides beyond the kesterite-based CZTSSe for PV applications. In this review, we summarize the above recent efforts and attempts in both state-of-the-art experimental studies and gaining new theoretical insights to alleviate the problems associated with CZTSSe, as well as learn a lesson for applying to other promising chalcogenide PV materials. In addition, the record efficiencies for cation-substituted kesterite and related chalcogenides PV devices reported till date have been summarized in this review. Finally, a summary and outlook are provided on the current research trends in relation to improving kesterite-based devices, as well as the exploration of related chalcogenides PV materials.