Introduction Fixed dose combinations (FCs) represent a potentially valuable treatment strategy in glaucoma management. Fixed combinations not only improve adherence by reducing the medication burden, but also decrease the total amount of potentially deleterious preservatives an eye is exposed to. Areas covered We provide a critical review of selected evidence on both the safety and tolerability of presently available and emerging glaucoma FCs. There is convincing short-term safety and tolerability evidence on intraocular pressure (IOP)-lowering FCs compared to that of monotherapies and, to a lesser degree, to that of concomitant, equivalent combination therapies. In contrast, there is a scarcity of trials evaluating the long-term efficacy and safety of glaucoma FCs and no conclusive data on the reduction of adverse events with FCs. Expert opinion It is vital for clinicians to carefully weigh the efficacy, safety, tolerability, and adherence of IOP-lowering FCs. Given the number of currently available and emerging FC therapy options in glaucoma, as well as the complexities of incorporating them in the various combination therapy regimens, successful stepwise therapy remains often elusive.