Clostridium difficile infection (CDI) seems to be changing-with increasing virulence and incidence, more resistance to metronidazole, and worse outcomes. Accurate diagnosis is critical, but 3 common misconceptions lead to misdiagnosis: Clostridium difficile infection is a possibility when the patient has fewer than 3 loose stools per day; the glutamate dehydrogenase test for CDI is sensitive and thus is a good initial test; and repeating an insensitive laboratory test for CDI is useful. These misconceptions can lead to missed diagnoses (for example, when tests with low sensitivity are used) and to false diagnoses (for example, when tests are done in patients who are unlikely to have CDI because they have minimal diarrhea or negative results on recent tests). Diagnoses of CDI will be more accurate if clinicians use tests with a higher sensitivity, reduce the frequency of testing for a single episode of diarrhea, and give more attention to key elements of the patient's history.