Sepsis is the leading cause of death among critically ill patients in intensive care units, and treatment options are limited. Therapies developed against the proinflammatory stage have failed clinically; therefore, new approaches that target the host immune response in sepsis are necessary. Increasing evidence suggests that a major pathophysiological event in sepsis is immune suppression, often resulting in secondary fungal, bacterial, or viral infections. Recent studies from animal sepsis models and patient samples suggest that cytokines such as interleukin-7 (IL-7), IL-15, granulocyte macrophage colony-stimulating factor (GM-CSF), as well as co-inhibitory molecule blockade, such as anti-programmed cell death receptor-1 (anti-PD-1) and anti-B and T lymphocyte attenuator (anti-BTLA), may have utility in alleviating the clinical morbidity associated with sustained sepsis. This review discusses some of these novel immunomodulatory agents and evaluates their potential use as therapeutics.