Chemotherapy has recently achieved a major role in the primary management of intraocular retinoblastoma. Tumor reduction by first-line chemotherapy (chemoreduction) followed by local treatments is now accepted as treatment strategy for intraocular retinoblastoma with the goal of avoiding external beam radiotherapy (EBRT) or enucleation. Although efficient in reducing tumor volume, chemotherapy cannot cure retinoblastoma. Different chemoreduction protocols are used to shrink the tumor, making it treatable with cryotherapy, laser photocoagulation, thermotherapy, and plaque radiotherapy. Systemic chemotherapy used with local ophthalmic therapies during or after the chemotherapy can eliminate the need for enucleation or external beam radiotherapy in Reese-Ellsworth group 1, 2, or 3 retinoblastoma. This combination is not sufficient to obtain tumor control in most eyes with large tumors and diffuse vitreous and subretinal seeds (Reese-Ellsworth group 4 and 5 tumors), and EBRT or enucleation is eventually required. The resultant visual acuity after globe-conserving therapies in those eyes with Reese-Ellsworth group 4 and 5 tumors is often poor. Preliminary results of a phase I/II study of subconjunctival carboplatin injection are encouraging. Enucleation is still recommended in situations such as eyes containing large tumors, long standing retinal detachment, neovascular glaucoma, pars plana tumor seeding, anterior chamber involvement or choroid, optic nerve or orbital tumor extension, and no expectation for useful vision. Chemoprophylaxis is necessary for patients with tumor extending to the surgical margin of the optic nerve and is likely beneficial in preventing metastases in patients with tumor extending beyond the lamina cribrosa. Intensified chemotherapy with autologous stem cell rescue appears effective for patients with metastatic retinoblastoma.