Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the leading adverse drug reactions during the course of tuberculosis treatment and poses a considerable challenge to clinicians and researchers. Previous studies have revealed the important contribution of drug metabolism and transporter enzymes to the complexity of ATDH. The emerging roles of immune response and oxidative stress resulting from reactive metabolite in the development of ATDH have also gained attention recently. Both non-genetic and genetic factors can have a significant impact on the susceptibility to ATDH, consequently altering the risk of hepatotoxicity in susceptible individuals. Non-genetic risk factors associated with ATDH include host factors, environment factors and drug-related factors. Genetic factors contributing to the susceptibility of ATDH involve genetic variations in bioactivation/toxification pathways via the cytochrome P450 enzymes (phase I), detoxification reactions by N-acetyl transferase 2, glutathione S-transferase and uridine diphosphate glucuronosyltransferase (phase II) and hepatic transport (phase III), together with immunological factors and antioxidant response. Better understanding of these factors may help to predict and prevent the occurrence of ATDH and develop more effective treatments. This review focuses on the mechanisms of ATDH and the key factors of susceptibility associated with drug metabolism, hepatic transport, immune response and oxidative stress.