Refining animal models of sepsis requires a multifaceted approach encompassing: 1) the development of more sophisticated and clinically relevant animal models that incorporate age, sex, polymicrobial infections, and comorbidities; 2) the integration of organ support technologies and multi-omics calibration; 3) the strategic use of multiple species; and 4) the selection of multiple more feasible therapeutic targets including HMGB1, CIRP, and pCTS-L. Here, HMGB1 is linked to infection.