ConspectusLithium-sulfur batteries (LSBs), recognized for their high energy density and cost-effectiveness, offer significant potential for advancement in energy storage. However, their widespread deployment remains hindered by challenges such as sluggish reaction kinetics and the shuttle effect of lithium polysulfides (LiPSs). By the introduction of catalytic materials, the effective adsorption of LiPSs, smooth surface migration behavior, and significantly reduced conversion energy barriers are expected to be achieved, thereby sharpening electrochemical reaction kinetics and fundamentally addressing the aforementioned challenges. However, driven by practical application targets, the demand for higher loadings and reduced electrolyte parameters inevitably exacerbates the burden on catalytic materials during their service. Additionally, given that catalytic materials contribute negligible electrochemical capacity, their incorporation inevitably increases the mass of nonactive components for reducing the energy density of LSBs. A meticulous insight into the lithium-sulfur catalytic reaction reveals that the conversion of LiPSs is dominated by active sites on the surfaces of catalytic materials. These microregions provide the necessary electron and ion transport for the conversion reaction of LiPSs, with their efficacy and quantity directly impacting the conversion efficiency. In light of these considerations, the strategic optimization of active sites emerges as a paramount pathway toward promoting the performance of LSBs while concurrently mitigating unnecessary mass. Here, we outline three strategies developed by our group to optimize active sites of catalytic materials: (1) Augmenting active sites by customizing structural modulation and precise dimensional control to maximize exposure. Emphasis has been placed on the approaches for material synthesis and the essence of reactions for achieving this strategy. (2) Regulating the microenvironment of active sites by integrating the coordination refinement, long-range atomic interactions, metal-support interactions, and other electronic regulation strategies, thereby providing an elevation in the intrinsic catalytic performance. (3) Implementing a self-cleaning mechanism for active sites to counteract deactivation by designing a tandem adsorption-migration-transformation pathway of sulfur contained within the molecular domain. Throughout this process, the intrinsic mechanisms driving performance enhancement through active site optimization strategies have been prominently emphasized, which encompass aspects such as electronic structure, atomic composition, and molecular configuration and significantly expand the comprehension of Li-S catalytic chemistry. Subsequently, considerations demanding heightened attention in future processes of active site optimization for catalytic materials have been delineated, including the in situ evolution patterns and resistance to the poisoning of active sites. It is noteworthy that given the similarity between Li-S catalysis chemistry and traditional electrocatalytic processes, this Account elucidates the concept of active site optimization by drawing insights from representative works and our own works in the field of electrocatalysis, which is relatively rare in previous reviews of LSBs. The proposed insights contribute to uncovering the intrinsic mechanisms of Li-S catalysis chemistry and introducing innovative ideas into active site optimization, ultimately advancing energy density and stability in LSBs.