Thermodynamic therapy (TDT) is a novel cancer therapy modality that has attracted a lot of attention in recent years. In this therapy, TDT reagents react to thermal stimulation (e.g., laser, ultrasound, microwave) to produce highly toxic alkyl radicals, which can kill cancer cells and inhibit tumor growth. These alkyl radicals may also activate an antitumor immune response, preventing distant metastasis. To improve tumor-targeted therapy efficiency, the TDT reagents are usually incorporated into organic or inorganic nanoparticles. This chapter summarizes the different types of TDT reagents, their mechanisms, and TDT reagent-loaded nanoparticles for cancer TDT and combination therapy (for example, TDT and photothermal therapy). The advantages and disadvantages of TDT are also discussed.