Endophthalmitis is an inflammatory reaction of intraocular fluids or tissues. Infectious endophthalmitis is one of the most serious complications of ophthalmic surgery. Occasionally, infectious endophthalmitis is the presenting feature of an underlying systemic infection. Successful management of infectious endophthalmitis depends on timely diagnosis and institution of appropriate therapy. Recognition of the different clinical settings in which endophthalmitis occurs and awareness of the highly variable presentation it may have facilitate timely diagnosis. Biopsy of intraocular fluid/tissue is the only method that permits reliable diagnosis and treatment. The different presenting clinical settings, a rational approach to diagnosis (i.e., when, what, and how to biopsy), and the treatment of infectious endophthalmitis are reviewed.