Ceramides, a class of sphingolipids, play crucial roles in regulating cellular processes such as apoptosis, proliferation, and metabolism. Deregulation of ceramide metabolism contributes to cancer development and progression. This review discusses the multifaceted roles of ceramides in cancer cells and strategies to modulate ceramide levels for cancer therapy. Ceramides attenuate cell survival signaling and metabolic pathways while activating apoptotic mechanisms, making them tumor-suppressive. Approaches to increase ceramide levels in cancer cells include using synthetic analogs, inhibiting ceramide degradation, and activating ceramide synthesis. Combination therapies, such as combining ceramide modulators with chemotherapies, immunotherapies, apoptosis inducers, and anti-angiogenics, offer synergistic antitumor effects. Ongoing clinical trials evaluate the potential of ceramide nanoliposomes and analogs. Challenges include the complexity of ceramide metabolism, targeted delivery, cancer heterogeneity, resistance mechanisms, and long-term safety. Despite these challenges, ceramide-based therapy holds promise for cancer treatment, but further research is needed to optimize its efficacy and safety.Ceramides, a class of sphingolipids, play crucial roles in regulating cellular processes such as apoptosis, proliferation, and metabolism. Deregulation of ceramide metabolism contributes to cancer development and progression. This review discusses the multifaceted roles of ceramides in cancer cells and strategies to modulate ceramide levels for cancer therapy. Ceramides attenuate cell survival signaling and metabolic pathways while activating apoptotic mechanisms, making them tumor-suppressive. Approaches to increase ceramide levels in cancer cells include using synthetic analogs, inhibiting ceramide degradation, and activating ceramide synthesis. Combination therapies, such as combining ceramide modulators with chemotherapies, immunotherapies, apoptosis inducers, and anti-angiogenics, offer synergistic antitumor effects. Ongoing clinical trials evaluate the potential of ceramide nanoliposomes and analogs. Challenges include the complexity of ceramide metabolism, targeted delivery, cancer heterogeneity, resistance mechanisms, and long-term safety. Despite these challenges, ceramide-based therapy holds promise for cancer treatment, but further research is needed to optimize its efficacy and safety.