Abstract Hypoxia due to rapid tumor growth with impaired neovascularization and inflammation resulting from immune cell activation are hallmarks of cancer. Hypoxia-inducible factors control transcriptional adaptation in response to low oxygen conditions, both in tumor and immune cells. In addition, sphingolipids become increasingly recognized as important cell mediators in tumor and inflammatory hypoxia. Recent studies have identified acid sphingomyelinase (ASM), a central enzyme in the sphingolipid metabolism, as a regulator of several types of stress stimuli pathways and an important player in the tumor microenvironment. Therefore, this review will address the connection between the hypoxic response and the ASM/ceramide system in the context of inflammatory hypoxia.