The diagnosis of appendicitis is fraught with potential pitfalls, and despite its prevalence, appendicitis continues to be a condition at high risk for missed and delayed diagnosis. There is no single historical or physical finding or laboratory test that can definitively make the diagnosis. This article discusses the value of presenting signs, symptoms, laboratory testing, and the rational use of various imaging modalities, such as CT scanning and ultrasound. Challenges of special populations, such as children, the elderly, and pregnant patients, are also discussed. Although appendicitis continues to be a source of medical legal risk and misdiagnosis, a clear understanding of the strengths and limitations of all tests in suspected appendicitis can improve the emergency physician’s diagnostic accuracy in this high-risk disease.