It is well known that tumor formation arises from the imbalance between cell death and proliferation. For many years, cancer research has engaged an important part of its efforts to find new therapeutic strategies based on cell death induction. One of the predominant ways to kill tumor cells is to trigger apoptosis by chemotherapy. However tumor responsiveness to chemotherapy is dependent on different biological factors including cancer types, genetics and pharmacogenetics. Although molecular mechanisms involved in chemotherapy-induced apoptosis are diverse and depend on cell-type and drugs used, a common pathway leading to tumor cell death has been shown to implicate the generation of a simple cellular sphingolipid, ceramide. Ceramide is released by the activity of neutral or acidic sphingomyelinases or de novo synthesis during treatment with chemotherapy. This review in particular focuses on enzymes involved in chemotherapy-induced cell death such as neutral or acidic sphingomyelinases and ceramide synthases, the role of ceramide in cellular effects of chemotherapy at the plasma membrane or the mitochondria and the induction of cell death by ceramide. It also includes recent advances on novel patented sphingolipid compounds and cancer therapeutic strategies based on ceramide release.