The vast majority of clinical and basic science research on the immune consequences of burn injury and sepsis conducted during the last three decades has focused mainly on the roles of macrophages, neutrophils and, to a lesser extent, conventional T lymphocytes. During recent years, however, it has become increasingly clear that minor subsets of innate immune cells, innate regulatory lymphocytes in particular, are central to processes involved in both protective immunity and immunopathology. Recent reports by our laboratory and others have just begun to shed light on the critical roles of innate lymphocyte subsets, including natural killer T cells, natural killer cells, gamma-delta T cells, and naturally occurring CD4+CD25+ regulatory T cells during the immune response to burn injury and sepsis. Given their emerging importance and documented upstream regulatory capacities over macrophage, dendritic cell, and T lymphocyte functions, innate regulatory lymphocytes represent attractive new targets for therapeutic intervention for the overall immune paralysis that occurs with injury and sepsis. Here, we provide an overview of the current state of knowledge of these particular cell subsets in the immune response to burn injury and sepsis.