Dry eye disease (DED) is a multifactorial and complex disease of the ocular surface, with a high prevalence in adults. We systematically reviewed efficacy and safety data from published articles reporting results from prospective, controlled trials of topical ophthalmic drugs for DED. PubMed was searched for articles from January 1997 to October 2017. Twenty-six unique trials investigating 13 ophthalmic drugs were identified, including trials of the approved drugs cyclosporine A, cyclosporine A cationic emulsion, diquafosol, rebamipide and lifitegrast. All identified studies provided level 1 evidence. None of the large (N > 100) studies demonstrated statistical significance of primary endpoints for both a sign and a symptom endpoint versus a control treatment in the same published trial. Publications on lifitegrast reported statistical superiority in a symptom or sign endpoint versus the control group in a large (N > 200), multicenter trial, with results repeated in trials of similar design. The most common adverse events associated with the approved drugs related to ocular discomfort upon instillation, especially burning/stinging and ocular irritation. The trial design and endpoints used across the studies varied considerably, highlighting the importance of standardization in clinical trials for DED. Recent advances in drug delivery and improved understanding of DED should contribute to new ophthalmic drug approvals.