Sight-threatening microbial keratitis associated with contact lens wear remains a serious concern for patients, eye-care practitioners, and the contact lens industry. Several decades of research and some major advances in lens and solution technology have not resulted in a decline in disease incidence. Here, we offer a perspective on the complex pathogenesis of microbial keratitis, the factors that have prevented a better understanding of this disease, and new approaches being used to tackle this important clinical problem.