Retinoblastoma was traditionally treated with enucleation and external-beam radiotherapy. However, in the past decade, systemic chemotherapy has become the primary globe-salvaging approach. This approach is generally combined with focal treatment, allowing for tumor consolidation following initial chemoreduction. A recently developed classification scheme may improve our ability to predict outcomes with this treatment modality. The Children’s Oncology Group has initiated a series of prospective multicenter trials to improve treatment outcomes with systemic chemotherapy.