In this review, we summarize the functions of acid sphingomyelinase in order to contribute to the question whether acid sphingomyelinase (ASM) is our friend or foe in the course of sepsis and severe infection, and further discuss the significance of both, an intended and an unattended inhibition for interpretation of results from preclinical and clinical studies with septic patients. Here, SMPD1 is linked to Sepsis.