Acid sphingomyelinase (ASM) is one enzyme responsible for the production of ceramide via the hydrolysis of sphingomyelin. Recent findings have revealed the important role of ASM in the initiation of ceramide-induced cell apoptosis, as well as in the pathophysiology of many common diseases (e.g. cardiovascular diseases, diabetes, pulmonary diseases, and neurological diseases). Other studies have also shown that ASM activation may occur through the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as well as by inflammatory mechanisms that may be induced by environmental and occupational stresses. ASM activation, in turn, may create excess or abnormally distributed ceramides, which could lead to tissue and organ injuries, including to the pulmonary, liver, kidney, and nervous systems. This review will discuss the basic biology of ASM and focus on the role and regulation of ASM in environmental stress responses. We propose that ASM activation is an important factor in environmental health, and that ASM-based therapeutics may have a key role in preventing environmental-induced tissue injury.