Nonalcoholic fatty liver disease(NAFLD) is the most common liver disease worldwide, affecting approximately one third of the Western world. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis(NASH), which consists of steatosis, ballooning injury and inflammation. Despite an alarming growth in the statistics surrounding NAFLD, there are as yet no effective therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic fatty liver to NASH. An immune response is triggered by countless signals called damage-associated molecular patterns(DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors(PRRs) on hepatic immune cells to initiate inflammatory signaling. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing potential therapies that target innate immune pathways, we have described a recent study that demonstrated that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. In addition to identifying a new ligand for TLR9 during NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which consists of steatosis, Despite an alarming growth in the statistics surrounding NAFLD, there are as no no therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic An immune response is triggered by countless signals called damage-associated molecular patterns (DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors (PRRs) on hepatic immune cells. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing p otential therapies that target innate immune pathways, we have described a recent study that that that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy.