Cataract formation during preclinical drug safety assessment studies can be a devastating safety finding during drug development based on the stage at which these findings usually occur. The lens explant culture models offer an extremely versatile and simple in vitro model to screen compound for such toxic liabilities or to study possible mechanisms of toxicity. The following chapter is designed to highlight numerous examples of cataract formation during the drug development process, techniques used to prepare the model and some approaches used to understand drug-induced cataract formation in vitro from a mechanistic, screening and species sensitivity perspective.