Pediatric cancer has a better outcome profile than adult cancers. However, refractory disease and the potential for long-term morbidity resulting from the use of conventional therapies necessitate the development of novel treatments for this population. Recent advances in oncology include the use of low dose metronomic (LDM) chemotherapy. The promise of this novel therapeutic approach includes reduced toxicity and the potential for efficacy predominantly through an antiangiogenic effect. The clinical benefit may be realized especially when combined with other antiangiogenic agents and/or conventional maximally tolerated doses of chemotherapy. In this article, we review the evidence for the use of LDM chemotherapy with a focus on pediatric cancer. Included are some of the possible risks attributable to this therapy in a pediatric setting and some of the hurdles to overcome in order to conduct good clinical research. Emphasis is placed on the development of proper surrogate markers to monitor antiangiogenic therapy in order to both optimize the dosing schedule for LDM chemotherapy and to provide a way of tracking therapeutic efficacy.