Non-alcoholic steatohepatitis (NASH) and associated end-stage liver disease is a growing cause of concern throughout the Western world. It constitutes a significant clinical burden for which therapeutic approaches are very limited. Over the last years, considerable attention has therefore been paid to identifying potential therapeutic strategies to reduce this burden. Annexin A1 (AnxA1), a calcium-phospholipid binding protein, has been proposed to be a negative regulator of inflammation in the context of NASH. In a recent publication, Gadipudi, Ramavath, Provera et al. investigated the therapeutic potential of Annexin A1 treatment in preventing the progression of NASH. They demonstrate that treatment of mice with NASH with recombinant human AnxA1 can reduce inflammation and fibrosis without affecting steatosis or metabolic syndrome. This was proposed to be achieved through the modulation of the macrophage populations present in the liver. Here, we discuss the main findings of this work and raise some outstanding questions regarding the possible mechanisms involved and the functions of distinct macrophage populations in NASH.