Sepsis, a life-threatening infection with organ dysfunction, triggers a complex interplay of pro-inflammatory and anti-inflammatory processes. The balance between these pathways determines the patient's fate. Despite the failure of many clinical trials, a better understanding of the pathophysiology and immunological phases of sepsis offers new treatment approaches. Biomarker-guided immunotherapy administered during the appropriate immune phase of sepsis is a promising advance. Sepsis is characterized by an initial hyperinflammatory phase followed by a protracted immunosuppressive phase, leading to death from failure to control primary infections or secondary hospital-acquired infections. Recent studies suggest that both pro-inflammatory and anti-inflammatory responses occur early and simultaneously, with the initial hyperinflammatory phase being dominant. However, a competing theory posits that persistent activation of the innate immune system drives uncontrolled inflammation and organ injury, leading to late deaths. The authors discuss the various defects in innate and adaptive immune cells caused by sepsis and highlight promising immunotherapies. These include recombinant human IL-7, which supports T cell development and function, and PD1 and PD1L1-specific antibodies, which block co-inhibitory molecules and improve survival in animal models of sepsis. Other potential treatments include recombinant interferon-γ (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which target monocytes and macrophages to enhance immune function. The authors emphasize the importance of identifying biomarkers to guide the use of immunotherapies, particularly in the immunosuppressive phase of sepsis. They also discuss the challenges and controversies in understanding the host immune response to sepsis, including the role of apoptosis and immunosenescence.Sepsis, a life-threatening infection with organ dysfunction, triggers a complex interplay of pro-inflammatory and anti-inflammatory processes. The balance between these pathways determines the patient's fate. Despite the failure of many clinical trials, a better understanding of the pathophysiology and immunological phases of sepsis offers new treatment approaches. Biomarker-guided immunotherapy administered during the appropriate immune phase of sepsis is a promising advance. Sepsis is characterized by an initial hyperinflammatory phase followed by a protracted immunosuppressive phase, leading to death from failure to control primary infections or secondary hospital-acquired infections. Recent studies suggest that both pro-inflammatory and anti-inflammatory responses occur early and simultaneously, with the initial hyperinflammatory phase being dominant. However, a competing theory posits that persistent activation of the innate immune system drives uncontrolled inflammation and organ injury, leading to late deaths. The authors discuss the various defects in innate and adaptive immune cells caused by sepsis and highlight promising immunotherapies. These include recombinant human IL-7, which supports T cell development and function, and PD1 and PD1L1-specific antibodies, which block co-inhibitory molecules and improve survival in animal models of sepsis. Other potential treatments include recombinant interferon-γ (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which target monocytes and macrophages to enhance immune function. The authors emphasize the importance of identifying biomarkers to guide the use of immunotherapies, particularly in the immunosuppressive phase of sepsis. They also discuss the challenges and controversies in understanding the host immune response to sepsis, including the role of apoptosis and immunosenescence.