Here, we paved a new way to evaluate the susceptibility of M-N 4 -based single-atom catalysts (SACs) to sulfur poisoning in Li-S batteries. The strong binding strength of M-S in Ti-N 4 - and V-N 4 -based SACs is attributed to the high bond order, pronounced d-p hybridization, and differential charge density. However, overly strong binding strength of M-S can create a high energy barrier that prevents the detachment of covered S atoms and induces sulfur poisoning. This can significantly impede the exposure of catalysts to residual reactants during subsequent charge-discharge cycles. Moreover, the sulfur poisoning will dramatically depress the overall catalytic performance of the SACs during the subsequent charge-discharge process, indicating that some compromise should be made between the high catalytic performance and the sulfur poisoning in designing SACs for Li-S batteries.