ABSTRACT: The treatment of children with low-grade glioma has evolved over the last several decades, beginning initially with focal radiotherapy, which has now been largely replaced by systemic treatment with conventional chemotherapy agents or more recently molecularly targeted therapeutics. A consensus standard of care is not well defined, leaving clinicians and parents to choose from an increasing number of options, often without complete information concerning the associated risks and benefits. Issues critical to this topic include timing of interventions (when to treat), preservation of neurological function (goals of treatment), choice of initial therapy strategy (conventional cytotoxic chemotherapy vs molecularly targeted therapy), duration of treatment (how long, and what clinical or imaging endpoints to consider), and perhaps most important, risk reduction relative to anticipated benefit. The groups from the University of California, San Francisco and Dana Farber Cancer Institute, moderated by Michael Prados, herein debate the merits of cytotoxic chemotherapy and targeted therapeutics as initial treatment strategies in pediatric low-grade glioma, a topic discussed daily in Tumor Boards across the United States and abroad. Prospective, randomized, phase 3 trials comparing the 2 strategies, conducted within homogenous disease settings, with consistently evaluated functional and imaging endpoints, are not available to guide the risks/benefit discussion. As is often the case in rare biologically diverse diseases, in a vulnerable population, therapy decisions are frequently based on incomplete data, physician experience, bias to some degree, and patient/family preference.