The cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH) is a transcription factor localized to the endoplasmic reticulum (ER) membrane. Previous studies have demonstrated that CREBH is activated by ER stress, hepatic glucose and lipid metabolism signaling, and inflammation. Thus, it may be critical in the regulation of various physiological functions associated with the development of non-alcoholic fatty liver disease (NAFLD), which results from inflammation and disorder of hepatic glucose and lipid metabolism. Therefore, CREBH may have potential as a pharmacological target for NAFLD. This review summarizes recent scientific developments and the biological actions of CREBH with a particular focus on its involvement in NAFLD.