One of the most essential methods of treating cancer is systemic chemotherapy. Several primary and secondary ophthalmologic cancers exist that benefit from treatment with chemotherapy. Most chemotherapy drugs have non-selective mechanisms of action against DNA, RNA, proteins, or metabolic pathways in tumor cells, but because of the non-selective properties of chemotherapy, normal cells are also affected. Chemotherapy is often given in combination with other agents to enhance cytotoxic effects, combat multi-drug resistance, and reduce the risk of relapse. Systemic chemotherapy is given intravenously in repetitive cycles at maximum tolerated doses in order to allow for a constant fraction of tumor cell kill and to allow for recovery of affected normal cells. Antineoplastic drugs have the narrowest therapeutic window of any class of drugs, so the treating physician must balance the risk of toxicities against the risk of relapse in choosing chemotherapy regimens for patients with ophthalmologic cancers. This chapter will discuss the basic principles of systemic chemotherapy, review some of the commonly used treatment regimens for ophthalmologic cancers, and review common toxicities of chemotherapy.