Sphingolipid biosynthesis and breakdown in yeast share many homologies in their pathways with higher eukaryotes (Dickson, R. C. 1998. Sphingolipid functions in Saccharomyces cerevisiae: comparison to mammals. Annu. Rev. Biochem. 67: 27-48). In mammals, ceramide can be generated through hydrolysis of sphingomyelin catalyzed by sphingomyelinase (SMase). To date, as many as five SMases have been identified molecularly, separated into three main groups: acid, alkaline, and neutral SMases (nSMases) (Marchesini, N., and Y. Hannun. 2004. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem. Cell Biol. 82: 27-44). nSMase in mammals is represented by its homolog, inositol phosphosphingolipase C, codified by ISC1 in Saccharomyces cerevisiae (Sc) and Cryptococcus neoformans (Cn) and by CSS1 (Can't Stop Synthesizing cell wall) in Schizosaccharomyces pombe (Sp). Yeasts do not have sphingomyelin but instead have inositol phosphosphingolipids, which may function as orthologs of mammalian sphingomyelin. In this review, we will describe findings related to the function of ISC1, its localization, mechanisms, and its roles in cell response to different types of stresses. These studies serve as a foundation for the elucidation of the properties and functions of the extended family of nSMases.