Sepsis is a life-threatening medical condition caused by a dysregulated immune response to infection. It involves a heterogeneous process resulting in variable outcomes ranging from recovery to death and long-term immune paralysis. We are employing immune profiling to understand how an individual’s immune set-point and infection history drive sepsis trajectories. We are performing single-cell transcriptional profiling of the immune response to sepsis in patients to understand the basis for immune dysregulation. Using forward genetics screens, we seek to understand the molecular and cellular immune mechanisms that determine disease severity and that underlie immune sequelae to inform the development of biomarkers and targeted clinical interventions.