Medical treatment of ophthalmic diseases relies primarily on the use of multidose drugs. Short term use is highly effective usually with little local toxicity. However, chronic use of these preparations not only increases the likelihood of microbial contamination and secondary ocular infection, but also of toxicity from the drug formulation itself. Increasing awareness of the toxicity of ophthalmic preservatives has led to an increasing variety of preservative schemes ranging from “selfpreservation” to ionic buffer systems. For most of these systems, the anti-microbial efficacy of these systems, beyond outdated mandatory testing methods, is poorly defined, potentially placing these preparations at an unknown risk of contamination by unmonitored organisms. No uniformity in toxicity testing exists which further complicates the clinician’s judgment of the risk-benefit of using a particular drug formulation. In this manuscript we examine in detail each of the current employed ophthalmic preservative regimens with respect to their known antimicrobial activity and potential toxicity, where known. We also survey the most popular ophthalmic preparations, detailing their preservation schemes as well as concentrations to help the clinician in choosing an appropriate formulation for the treatment of various ophthalmic diseases.