Treatment of retinoblastoma must be individualized. Most patients with unilateral, non-metastatic retinoblastoma can be cured with enucleation alone. In patients with histologic risk factors, adjuvant chemotherapy is recommended, with the addition of orbital radiation for patients with trans-scleral involvement or tumor present at the level of the cut end of the optic nerve. Patients with metastases require intensive chemotherapy and consolidation with autologous hematopoietic stem cell rescue. Patients with bilateral or multifocal disease represent a major challenge. Cure of the disease is the first priority, but the therapeutic approach also has to consider eye and vision preservation. The approach is conservative, and only eyes with very advanced disease are enucleated upfront. Patients are treated with chemotherapy and intensive focal treatments, with the aim of delaying or avoiding radiation therapy and enucleation. For patients with early intraocular stage (Reese-Ellsworth groups I-III and International Groups A-B), the two-drug combination of vincristine and carboplatin is recommended. Patients with more advanced intraocular disease (Reese-Ellsworth groups IV-V and International Groups C-D) require more intensive chemotherapy. Standard of care for these patients incorporates etoposide into the regimen. Effective agents with good intraocular penetration, such as topotecan, are being investigated. Because most failures are secondary to progression of the vitreous seeds, subconjunctival carboplatin is added in cases with poor response of the vitreous tumors. Patients must be monitored very closely, with examinations under anesthesia every 4 to 6 weeks, and focal treatments are applied during the procedure. These include cryotherapy for small anterior tumors, thermotherapy and laser photocoagulation for small posterior tumors, and brachytherapy for larger tumors. New treatment approaches under development include the refinement of periocular chemotherapy administration using slow-release devices, the use of suicide gene therapy with local delivery of the herpes simplex thyrosine kinase gene (followed by systemic administration of ganciclovir), and the development of smallmolecule inhibitors of the MDMX-p53 interaction.