Assigning causality in drug-induced liver injury (DILI) due to a particular medication or herbal and dietary supplement relies on clinical history, exclusion of competing causes, prior reports of DILI, and judgment-no objective laboratory or histological tests exist to confirm a diagnosis of suspected DILI. Current causality assessment instruments are based on algorithmic scoring systems but are not widely used. Expert opinion remains the gold standard, but is cumbersome and has limited reproducibility. The lack of a valid and widely available causality assessment method hinders the identification of genetic and biochemical markers that may help better define DILI. Emerging technologies in pharmacogenomics and toxicogenomics may identify such markers if well-defined DILI cases and controls can provide tissue samples for analysis. In this article, current causality assessment instruments, including expert opinion, are discussed, and the necessary features for an improved instrument are provided.