Glaucoma is one of the leading causes of blindness worldwide. Increased intraocular pressure (IOP) is considered to be the most important risk factor. Major outcome studies from recent years have shown that lowering IOP is beneficial in primary open-angle glaucoma and ocular hypertension. The introduction of new classes of IOP-lowering drugs (alpha(2)-adrenoceptor agonists, topical carbonic anhydrase inhibitors and hypotensive lipids) in the last decade has contributed to a change in the drug prescription pattern. Together with beta-adrenoceptor antagonists (beta-blockers), these drugs are now considered to be first-choice classes, giving ophthalmologists ample opportunities to choose from a broad spectrum of IOP-lowering drugs. The number of possible medical treatment combinations has increased likewise.We review medical treatment combinations of two, three or four drugs from the four major first-choice glaucoma drug classes and provide an overview of the scientific evidence for IOP efficacy of second-line medical options when first-line therapy has been effective but additional IOP lowering is necessary. A systematic search of the literature initially revealed 2729 publications. After a thorough selection process, 42 studies were found to be eligible for inclusion in the review. Publications were excluded if the primary endpoint of the study was not IOP or if glaucoma topics other than IOP lowering of drugs were studied. In addition, studies that reported results for monotherapies only were excluded. The vast majority of study arms reported on combinations of a beta-blocker with either a carbonic anhydrase inhibitor or a hypotensive lipid. For a number of treatment combinations no eligible studies were available or could be included.This review shows that combining drugs from the different first-choice classes results in an additional IOP decrease. The exact magnitude of this additional decrease and the patients to whom it applies remain unclear. In many studies, no information on IOP before the run-in phase was available. However, such data are important in order to determine whether patients with high untreated IOP or patients non-responsive to the run-in drug(s) were preferentially included. Another issue that hampers interpretation is the fact that the timepoints of measurements of IOP before and after adding a drug should be related to the peak and trough times of the drugs. Finally, differences between concomitant use and fixed combined use of drugs may have consequences for the interpretation of results.