The liver regulates glucose and lipid metabolism, and under pathophysiological conditions such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) these processes become dysfunctional. Stress responses activate the hepatic MAPKs, and this is thought to impair insulin action and lipid metabolism. However, the MAPKs also activates MAPK phosphatase-1 (MKP-1) which oppose their actions. How the MAPK/MKP-1 homeostasis is controlled in liver metabolism remains unclear. Recent advances from this lab on how the MKP-1 functions to coordinately regulate MAPK signaling in hepatic metabolism reveals new modes through which MKP-1 acts as a nodal regulator of hepatic MAPK function by coupling to energy sensing pathways. We propose that MKP-1 may represent an unanticipated target for the treatment of liver diseases such as NAFLD.