Iron-sulfur clusters are ancient cofactors that play crucial roles in myriad cellular functions. Recent studies have shown that iron-sulfur clusters are closely related to the mechanisms of multiple cell death modalities. In addition, numerous previous studies have demonstrated that iron-sulfur clusters play an important role in the development and treatment of cancer. This review first summarizes the close association of iron-sulfur clusters with cell death modalities such as ferroptosis, cuprotosis, PANoptosis, and apoptosis and their potential role in cancer activation and drug resistance. This review hopes to generate new cancer therapy ideas and overcome drug resistance by modulating iron-sulfur clusters.