Sphingomyelin synthase (SMS), which comprises of two isozymes, SMS1 and SMS2, is the only enzyme that generates sphingomyelin (SM) by transferring phosphocholine of phosphatidylcholine to ceramide in mammals. Conversely, ceramide is generated from SM hydrolysis via sphingomyelinases (SMases), ceramide de novo synthesis, and the salvage pathway. The biosynthetic pathway for SM and ceramide content by SMS and SMase, respectively, is called “SM cycle.” SM forms a SM-rich microdomain on the cell membrane to regulate signal transduction, such as proliferation/survival, migration, and inflammation. On the other hand, ceramide acts as a lipid mediator by forming a ceramide-rich platform on the membrane, and ceramide exhibits physiological actions such as cell death, cell cycle arrest, and autophagy induction. Therefore, the regulation of ceramide/SM balance by SMS and SMase is responsible for diverse cell functions not only in physiological cells but also in cancer cells. This review outlines the implications of ceramide/SM balance through “SM cycle” in cancer progression and prevention. In addition, the possible involvement of “SM cycle” is introduced in anti-cancer tumor immunity, which has become a hot topic to innovate a more effective and safer way to conquer cancer in recent years. •SM cycle consisting of SMase and SM synthases plays a role in cancer progression and prevention.•Ceramide-rich platforms are important membranous scaffolds in ceramide-mediated cellular functions.•SM generated by SM synthases (SMSs) forms the SM-rich microdomain and plays the essential role in proliferation/survival, migration, chemoresistance, and inflammation in cancer.•SM cycle regulated by SMase and SMS is related in cancer progression and prevention.