AbstractSepsis is a global health priority, yet effective host‐directed targeted therapies have not been identified outside of the setting of coronavirus disease 2019 (COVID‐19). Lymphopenia occurs in up to ~52% of patients with sepsis and is associated with a higher mortality at both 30 and 100 days. In COVID‐19, the presence of lymphopenia correlates with intensive care unit admission, acute respiratory distress syndrome and death. The mechanisms underpinning lymphopenic sepsis remain unknown, and while high rates of lymphocyte apoptosis have been implicated, the relative contributions of cellular trafficking to inflamed tissues and reduction in lymphopoiesis require investigation. Further delineation of these underlying mechanisms holds the potential to open new avenues for the development of host‐directed therapies in lymphopenic sepsis. These may include recombinant cytokines (e.g. interleukin‐7), monoclonal antibodies (e.g. anti‐interleukin‐1, anti‐programmed cell death protein 1) and small interfering RNA (e.g. targeting interleukin‐10, transforming growth factor beta). Applying the frontier tools of translational cellular and genomic medicine to understand lymphopenia in the setting of critical infections holds the potential to significantly reduce the excessive global burden of sepsis.