Multidrug resistance (MDR) has become a major challenge in cancer therapy, it results in the failure of chemotherapy and anticancer drug development. Chemodynamic therapy (CDT), an emerging cancer treatment strategy, has been reported as a novel approach for cancer treatment characterized by low toxicity and minimal side effects. By generating robust cytotoxic hydroxyl radicals (·OH) via Fenton/Fenton-like reaction, CDT may cause cellular damage and oxidative stress-induced cell death. In recent years, many therapies based on CDT and/or combined with other treatment modalities are reported and exhibit exciting treatment efficacy in cancer treatment, such as photothermal therapy, photodynamic therapy, sonodynamic therapy, chemotherapy, starvation therapy and gas therapy etc. These combination therapies exhibit synergistic effects, significantly improving anticancer outcomes compared to CDT alone. Herein, we provide a comprehensive overview of CDT-based strategies in cancer treatment, highlighting developments of CDT and CDT-based combination strategies in tumor therapy, especially in overcoming MDR challenges. Finally, the opportunities and challenges of CDT and CDT-combination therapy in the clinical application are also addressed.