Zebrafish (Danio rerio) larvae are a uniquely powerful model system which investigate the effects of toxicant exposure on liver development and function. Manufacturing processes and development of new synthetic compounds increased rapidly since the middle of the twentieth century, resulting in widespread exposure to environmental toxicants. This is compounded by the shift in the global burden of disease from infectious agents to chronic disease, particularly in industrialized nations, which increases the need to investigate the long-term and transgenerational effects of environmental exposures on human health. Zebrafish provide an excellent model to investigate the mechanisms of action of environmental pollutants given their large-scale embryo production and rapid development, which allow for short-term assessment of toxicity in a whole animal system. Here we describe methods for the use of zebrafish to study hepatotoxicity and liver disease induced by chemical toxicants. Many of the genetic, molecular, and cellular processes are conserved between zebrafish and mammals, enabling translation to human populations and diseases.