Systemic chemotherapy, applied in conjunction with local therapy, is currently one of the main therapeutic options in retinoblastoma management. Chemotherapy has become popular in the management of retinoblastoma due to the mutagenic potential of external beam radiation. Current indications for systemic chemotherapy include metastatic disease, patients with high risk pathologic risk factors (PRF), patients with bilateral retinoblastoma to reduce the risk of developing pinealoblastoma and to reduce the size of large tumors and increase likelihood of globe salvage. Which patients with PRF would benefit from adjuvant chemotherapy is a matter of debate that will hopefully be resolved with greater standardization and inter-institution collaboration. High dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) show promise in increasing survival rates of metastatic retinoblastoma including CNS disease, which is nearly universally fatal. While chemotherapy is a powerful tool in treating retinoblastoma, it is associated with significant toxicity, has mutagenic potential and may increase the risk for systemic spread by delaying enucleation. These must be kept in mind when determining the best course of treatment.