General mechanisms proposed to account for the antitumor effects of low-dose metronomic chemotherapy. Some of the effects illustrated are mediated preferentially or selectively by certain chemotherapy drugs, e.g., cyclophosphamide and gemcitabine, which can inhibit T regulatory (T-regs) cells or myeloid-derived suppressor cells (MDSCs), respectively, and hence stimulate antitumor immunity. Metronomic chemotherapy using several chemotherapy drugs can inhibit angiogenesis or vasculogenesis through direct endothelial cell (EC) killing or suppression of bone marrow–derived endothelial progenitor cells (EPCs). Low-dose topoisomerase II poisons, such as topotecan, can suppress HIF-1α expression, and low-dose cyclophosphamide can upregulate antiangiogenic endogenous molecules, e.g., TSP-1. The results presented in the report by Chan et al. (2016) implicate a new mechanism involving affecting fibroblastic elements of the tumor stroma, which in turn can prevent and even suppress the TIC subpopulation normally increased by conventional MTD chemotherapy.