Drug-induced liver injury is the leading cause of acute liver failure in the United States, but the ability to ascribe hepatic injury confidently to a specific drug remains a challenging and often difficult pursuit. This article explores the ongoing challenges inherent in what is currently a clinical process of elimination made in the attempt of assigning causality in drug-induced liver injury. In particular, it points out the shortcomings and pitfalls that often limit the applicability of the causality-assessment methodologies currently in use.