Over the last decade, metronomic chemotherapy (MC)—the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration, at close regular intervals, with no prolonged drug-free breaks—has emerged as a potential strategy to control advanced/refractory cancer disease. It was originally believed to work primarily through anti-angiogenic mechanisms, but recently, other mechanisms of action have been reported. MC has the property to kill resistant cancer cells and/or to hamper tumor growth while significantly reducing unwanted toxic side effects. Here, we will expose preclinical data about MC and will briefly review the data regarding clinical experience with this kind of anti-cancer treatment in children. Based on these data, we will foresee potential new developments in MC in pediatric oncology, with an emphasis on countries with limited resources.