The 21st century has seen a steadily increasing social awareness of animal suffering, with increased attention to ethical considerations. Developing new integrated approaches to testing and assessment (IATA) strategies is an Organisation for Economic Co-operation and Development (OECD) goal to reduce animal testing. Currently, there is a lack of alternative models to test for ocular surface toxicity (aside from irritation) in lieu of the Draize eye irritation test (OECD guideline No. 405) performed in rabbits. Five alternative in vitro or ex vivo methods have been validated to replace this reference test, but only in combination. However, pathologies like Toxicity-Induced Dry Eye (TIDE), cataract, glaucoma, and neuropathic pain can occur after exposure to a pharmaceutical product or chemical and therefore need to be anticipated. To do so, new models of lacrimal glands, lens, and neurons innervating epithelia are required. These models must take into account real-life exposure (dose, time, and tear film clearance). The scientific community is working hard to develop new, robust, alternative, in silico, and in vitro models, while attempting to balance ethics and availability of biological materials. This review provides a broad overview of the validated methods for analyzing ocular irritation and those still used by some industries, as well as promising models that need to be optimized according to the OECD. Finally, we give an overview of recently developed innovative models, which could become new tools in the evaluation of ocular surface toxicity within the scope of IATAs.