Acute bloody diarrhea should be considered a medical emergency. Its causes are frequently serious or actionable or both and are usually identified. However, acute bloody diarrhea as a stand-alone clinical presentation has received little scholarly attention in the past several decades. Although the range of possible causes of acute bloody diarrhea is broad, infectious considerations are paramount and should always be prioritized in the evaluation of such patients. History, examination, and laboratory testing should be focused on minimizing time to diagnosis (and, by extension, to implementing appropriate therapy). Strategically chosen tests and imaging, avoidance of extraneous diagnostic pursuits, and provision of supportive care while awaiting diagnostic clarity are central to the adroit management of patients with acute bloody diarrhea. Diagnostic considerations differ somewhat between adults and children but have many elements in common, including the need for vigilance in detecting Escherichia coli O157:H7 infection. In this review, we discuss diagnostic approaches (emphasizing the importance of rapid, accurate, and thorough microbiologic investigation) and measures that can be taken to support patients while awaiting information that determines the cause of their disease. These topics are discussed in the context of the medical care that is available to children and adults with bloody diarrhea in most institutions in developed nations.