The sphingolipids are a class of lipids that serve as integral components of eukaryotic cell membranes (21, 49). Although previously considered to be simply structural molecules, sphingolipids have more recently been shown to act as signaling molecules in many cellular functions and to play crucial roles in the regulation of pathobiological processes, such as cancer, cardiovascular and neurodegenerative disorders, and inffammation or infectious diseases. In mammalian cells, ceramide, sphingosine, sphingosine-1-phosphate, and glucosylceramide are the most studied sphingolipids, and they regulate important processes, including the stress response, cell proliferation, apoptosis, angiogenesis, genetic diseases, and resistance to chemotherapy (7, 51, 80, 103, 105, 120). In other eukaryotes, such as fungi, sphingolipids have been implicated in the heat stress response (59, 110), endocytosis (97, 151), signal transduction (104), apoptosis (11), and fungal pathogenesis (11, 83). Interestingly, a mathematical model interconnecting the sphingolipid intracellular network has recently been proposed in the nonpathogenic fungus Saccharomyces cerevisiae (2); however, whether this interconnection is also present in pathogenic fungi or in mammalian cells awaits further investigations. In the area of microbial pathogenesis, sphingolipids play a role in the regulation of the delicate balance between the microbe and the host. Microorganisms that do not produce sphingolipids, including most bacteria and viruses, are able to utilize host sphingolipids to promote their virulence. Thus, in the context of bacterium-and virus-host interaction, the host is typically the source of sphingolipids, whereas in the context of the protozoan-and fungus-host interaction, both host and pathogen sphingolipids are involved. The determination of which sphingolipid (s)(host, microbe, or both) modulate the host-parasite interaction is particularly significant not only because it may provide important insights into the development of new therapeutic strategies but also because the outcome of this sphingolipid interaction may either lead to commensalism or to host damage/disease (9), thus expanding the function of a specific sphingolipid outside of the organism from which it originated. For instance, a mammalian sphingolipid acquired by a microbe may be used to exert a novel or different function through conversion by microbial enzyme into new sphingolipids or by hiding microbial cells from the host immune response and allowing colonization or dormancy without damage to the host. On the other hand, a microbial sphingolipid acquired by the host may interfere with host intracellular signaling and thereby alter the removal and destruction of the microbial cell, or it may elicit an autoimmune response through molecular mimicry. The goal of this review is to introduce and discuss microbial sphingolipids and their corresponding metabolizing enzymes as regulators of pathogenesis and to propose new hypotheses and perspectives toward a better understanding of the host-microbe interaction mediated by sphingolipids.