Infectious keratitis is a medical emergency resulting in significant visual morbidity. Indiscriminate use of antimicrobials leading to the emergence of resistant or refractory microorganisms has further worsened the prognosis. Coexisting ocular surface diseases, delay in diagnosis due to inadequate microbiological sample, a slow-growing/virulent organism, or systemic immunosuppressive state all contribute to the refractory response of the ulcer. With improved understanding of these varied ocular and systemic factors contributing to the refractory nature of the microbes, role of biofilm formation and recent research on improving the bioavailability of drugs along with the development of alternative therapies have helped provide the required multidimensional approach to effectively diagnose and manage cases of refractory corneal ulcers and prevent corneal perforations or further dissemination of disease. In this review, we explore the current literature and future directions of the diagnosis and treatment of refractory keratitis.