The clinician plays a key role in the detection and diagnosis of adverse drug reactions (ADRs). The diagnosis of ADRs, however, is a complex task. In the past, there were no systematically applied diagnostic criteria for ADRs, no formal methods of case analysis, no standardized epidemiologic approaches, and a limited knowledge of mechanisms. This resulted in the overdiagnosis of ADRs, which has negative consequences such as limiting treatment options. Recently, there have been various improvements in the diagnosis of ADRs, such as the development of standardized decision aids and of in vitro diagnostic tests. This article briefly reviews some of this knowledge, discusses the role of in vivo and in vitro rechallenge, and summarizes a probabilistic approach for collecting relevant information and diagnosing ADRs. The intention is to increase awareness of the different approaches for diagnosing ADRs as well as to stimulate researchers to continue to collect pharmacoepidemiologic information, study the pharmacologic, immunologic, and genetic factors involved in the pathogenesis of drug reactions, and develop and test new diagnostic instruments under various clinical conditions.