Background: Chemotherapeutic resistance and local recurrence or distant organ metastasis are the major causes of cancer mortality. Conventional cancer treatments do not consistently prevent cancer recurrence.; Methods: We illustrate the key roles that cancer stem cells and the tumor microenvironment-particularly the lymph node stromal microenvironment-play in tumor drug resistance, metastasis, and recurrence in 2 representative cancers: colorectal cancer and follicular lymphoma.; Conclusion: We believe that combination treatment with chemotherapeutic agents in conjunction with targeted therapies, such as stromal/cancer stem cell signaling-targeted therapy, may effectively minimize cancer recurrence.