Achieving an effective antimicrobial concentration of a broad spectrum drug by conventional oral or topical route is limited by the barriers of the eye. Systemic drugs are often underused or exploited for ocular use without rationalizing the penetration characteristics of the drug. Lack of clarity or consensus about the underlying mechanisms of drug penetration into the eye translates into attenuated enthusiasm among pharmaceutical researchers and ophthalmic clinicians. This review summarizes the available literature on intraocular penetration of ciprofloxacin following different application routes, mainly systemic administration, and the rationale for its use in intraocular infections.