Members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors are players of substantial relevance in the regulation of hepatic gene expression. NRs direct normal physiology and metabolism, adaptations to liver disease, and responses to inflammation and toxins.They also contribute to the regenerative response. In this review, we summarize currently available experimental and clinical data, focusing on the role of NRs in cholestasis and nonalcoholic fatty liver disease (NAFLD). We also highlight the potential of NRs as targets for safe and effective therapeutic interventions.