TOSO (also known as FAIM3) is expressed on the cell surface of B cells and activated T cells and has been suggested to be the Fc receptor for IgM. Lang et al. now report that TOSO is also expressed by monocytes and granulocytes and is crucial for their function. Following stimulation, Toso−/− granulocytes showed enhanced degranulation and reactive oxygen species generation compared with wild-type controls. Moreover, Toso−/− monocytes and granulocytes had defective phagocytosis and delayed activation of nuclear factor-κB in response to lipopolysaccharide (LPS). In contrast to wild-type mice, Toso−/− mice were resistant to LPS-induced sepsis as a result of low cytokine expression. However, Toso−/− mice failed to control Listeria monocytogenes infection, and the high bacterial titres led to increased lethality compared with infected wild-type controls. Thus, TOSO is a regulator of innate immune responses.