Appendectomy is the most commonly performed emergency surgical procedure. Even in the era of laparoscopic surgery and modern computed tomography, the rate of negative appendectomies, defined as the removal of a non-inflamed appendix, remains high (10–15%). The general problem and incidence, as well as the influence of modern diagnostic modalities on the rate of negative appendectomies are of particular clinical relevance. Several clinical scoring systems have been developed, but they did not find their way into the daily clinical routine. A proposed diagnostic algorithm could support further efforts to reduce the rate of negative appendectomies. The risk of overtreatment in the reduction of the negative appendectomy rate might potentially lead to acceptance of a higher perforation rate.