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Ocular disposition and bioavailability of instilled drugs depend on the anatomy and physiology of the ocular surface as well as the physicochemical properties of the active agent. Intraocular bioavailability is positively associated with the amount of drug available onto the ocular surface and the precorneal residence time. Concerns are raised regarding systemic absorption of the instilled drugs intraocularly, percutaneously, via the conjunctiva, through the nasolacrimal system, or through the nasal, oral, and gastrointestinal mucosa. Special considerations exist regarding the anatomical features and the limited pharmacokinetic data on the pediatric population that complicate further the efficacy and systemic toxicity of the instilled medications. Both preclinical and clinical studies propose the reduction of the instilled drop volume, in the form of microdrops, as a means to enhance intraocular bioavailability of topically applied drugs, while minimizing patient discomfort and systemic adverse events. We summarize existing data on the clinical application of microdrops in a wide age range, from preterm infants to elderly adults. 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