Drug‐induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3‐5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug‐induced liver injury (DILI): antimicrobials; and central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro . These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug‐induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high‐risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high‐risk drugs. Conclusion : For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) patients are fully informed and consent, can adhere to follow‐up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases. (H epatology 2017;66:646–654).