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Dry eye disease (DED), a multifactorial disorder of the ocular surface and tear film, affects 5-50% of the global population. Currently, no satisfactory treatments of DED exist. Ongoing efforts to identify novel therapeutic agents are handicapped by the limitations of its preclinical animal models, which to some extent reflect the pathophysiological complexities of DED..  A plethora of DED models employing multiple animal species (mice, rats, cats, rabbits, dogs, and non-human primates) has been reported, each aiming to capture components of DED that appear to determine its pathophysiology and response to novel treatments. Here, we review the main animal models of DED and attempt to place each in the context of drug discovery. We also discuss a nascent method for ex vivo culture of human conjunctival cells that may abbreviate early screening of candidate therapeutics. Despite the remaining challenges, there is justified optimism that with the contribution of these preclinical models, the development of an efficacious and safe treatment of DED will be forthcoming.