There is a large body of evidence from clinical and experimental studies that the long-term use of topical drugs may induce ocular surface changes, causing ocular discomfort, dry eye, conjunctival inflammation, subconjunctival fibrosis, corneal surface impairment, and, as a consequence of chronic ocular surface changes, the potential risk of failure for further glaucoma surgery. Subclinical inflammation has also been widely described in patients receiving antiglaucoma treatments for long periods of time, with inflammatory cell infiltration and fibroblast activation in the conjunctiva and subconjunctival space. The preservative, especially benzalkonium chloride, which has consistently demonstrated its toxic effects in laboratory, experimental, and clinical studies, could induce or enhance such inflammatory changes. As a quaternary ammonium, this compound causes tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, corneal nerve impairment, chronic inflammation and potential damage to deeper ocular tissues. Drug-induced adverse effects are therefore far from being restricted to only allergic reactions, but they are often very difficult to identify because they mostly occur in a delayed or poorly specific manner, and result from complex and multifactorial interactions between the drugs and the ocular surface. Postoperatively, the ocular surface also plays an important role, as the conjunctiva interacts with aqueous humor and subconjunctival fibrosis may block aqueous outflow and cause surgical failure. As preoperative inflammation underlies postoperative fibrosis and therefore surgical outcome, a better knowledge of ocular surface changes with appropriate evaluation and management should thus become a new paradigm in glaucoma care over the long term.