Purpose of Review <p>Although eye drops are generally considered safe, their indiscriminate or prolonged use may trigger relevant local and systemic adverse effects, whether allergic or not. This brief review summarizes the various reported side effects of eye drops due to their active ingredients and/or excipients, and suggests how to prevent or avoid them.</p> Recent Findings <p>Many active ingredients in eye drops commonly cause contact sensitization, and some preservatives may contribute to epithelial cytotoxicity, iatrogenic dry eye syndrome, and severe contact reactions. Furthermore, topical ocular therapy has low bioavailability and requires high concentrations of active ingredients, which can result in overexposure and increased local and systemic side effects, particularly in young children and the elderly.</p> Summary <p>This brief review addresses the main local (ocular, palpebral, and periorbital) and systemic risks associated with the different components of eye drops, from active ingredients to preservatives, paying special attention to hypersensitivity reactions.</p>