Metronomic (antiangiogenic) chemotherapy refers to a form of dose dense chemotherapy involving close regular, even daily, administration of conventional chemotherapy drugs at relatively low doses over long periods in the absence of prolonged drug-free periods. Anti-tumor efficacy, which in some cases can be remarkably effective in various experimental mouse models of cancer, even in the absence of toxicity, is thought to be mediated mainly by antiangiogenic effects, either locally, by direct targeting of activated/dividing endothelial cells in the angiogenic tumor neovasculature, or systemically, by effects on circulating (bone marrow derived) endothelial progenitor cells (CEPs). However, additional mechanisms may also be involved, including stimulation of the immune system by targeting regulatory T cells, and possibly also direct effects on tumor cells—which could include the tumor stem cell(-like) subpopulation. Metronomic chemotherapy, because of its relatively nontoxic nature, is ideal for combination therapy using various targeted biologic agents, especially antiangiogenic drugs. Other promising combinatorial strategies include “doublet” metronomic chemotherapy using two different chemotherapy drugs, interspersing low-dose chemotherapy with higher bolus dose (BD) injections of the same drug, or short-course maximum tolerated dose (MTD) chemotherapy followed by long-term metronomic chemotherapy combined with a targeted biologic agent. Such combinations can sometimes have striking preclinical anti-tumor effects, even in models involving large primary tumors or widespread high-volume metastatic disease.