Infectious keratitis represents a significant cause of ocular morbidity in the United States. The work-up and treatment of presumed infectious keratitis (PIK) has changed in the past two decades. The development of newer topical antibiotics has enabled broad-spectrum antibiotic coverage with good tissue penetration. The majority of PIK cases respond well to this strategy. The small numbers of cases that do not respond to the treatment are the cases that offer a diagnostic and therapeutic challenge. This review will describe different algorithms that can be followed for the successful management of patients with difficult or progressive PIK. These algorithms are based on scientific work and on our empirical clinical experience. The review will also present three different clinical cases of PIK that were managed according to the algorithms presented in this review.