Chemotherapy serves as one of the most effective approaches in numerous tumor treatments but also suffers from the limitations of low bioavailability and adverse side effects due to premature drug leakage. Therefore, it is crucial to realize accurate on-demand drug release for promoting the application of chemotherapeutic agents. To achieve this, stimuli-responsive nanomedicines that can be activated by delicately designed cascade reactions have been developed in recent years. In general, the nanomedicines are triggered by an internal or external stimulus, generating an intermediate stimulus at tumor site, which can intensify the differences between tumor and normal tissues; the drug release process is then further activated by the intermediate stimulus. In this review, the latest progress made in cascade reactions-driven drug-release modes, based on the intermediate stimuli of heat, hypoxia, and reactive oxygen species, is systematically summarized. The perspectives and challenges of cascade strategy for drug delivery are also discussed.