Isoniazid (INH) is a synthetic anti-mycobacterial agent used to treat active or latent tuberculosis (TB). INH has been in clinical use for nearly 70 years and remains broadly utilized at the front line of anti-TB treatment. However, the potential for liver damage and even fulminant liver failure during INH-based TB treatment presents a major challenge for TB control programs worldwide. In this review, we discuss the hepatotoxic effects of INH and provide an overview of the mechanisms and their applications in prediction and prevention of INH hepatotoxicity in clinical practice.