Although most medications for ophthalmic disease are administered locally, systemic absorption occurs as the drug passes into the nasopharynx by way of the nasolacrimal duct and may lead to a significant exposure. Knowledge of the mechanism of action of the drug, extent of systemic exposure, and its corresponding risks are important factors that must be considered before prescription of any ophthalmic agent. The relative risk in turn depends on the agent prescribed, plasma levels achieved, and individual susceptibility factors. Judicious use of pharmacotherapy in the management of ophthalmic disease should minimize the risk-benefit ratio.