Given the high prevalence of the use of medications in daily practice and the large number of people taking antirheumatic agents, the risk of drug-drug interactions and of hepatotoxicity is of concern. Both old and new compounds show such a risk. Nonsteroidal antinflammatory drugs are widely used drugs with potential adverse hepatic reactions. Nonsteroidal antinflammatory drugs are responsible for an important aliquot of transaminase elevation in the general population. Genetic susceptibility to diclofenac hepatotoxicity has promoted the knowledge about drug-specific, class-specific reactions. Some drugs (sulfasalazine, azathioprine, and leflunomide) may cause acute liver injury, whereas other compounds (methotrexate) may cause chronic liver damage as the result of the interaction among drug, host and environmental factors. The tumor necrosis factor-alpha inhibitor, infliximab, is associated with typical drug-induced autoimmune hepatitis. Also, the other biological disease-modifying antirheumatic drugs are not free of potential hepatotoxicity. The diagnosis of drug-induced liver injury follows the exclusion of other causes, involves a temporal relationship between drug exposure and adverse event, and should consider the potential participation of the underlying rheumatic disease to event occurrence. This article also includes data regarding hepatotoxicity from our outclinic patients receiving biological disease-modifying antirheumatic drugs.