Metabolic dysfunction-associated steatotic liver disease (MASLD), which represents the most common cause of liver disease, is emerging as a major health problem around the world. However, the molecular events that underline the pathogenesis and the progression of MASLD remain to be fully elucidated. Advanced stages of MASLD is strongly associated with liver-related outcomes and overall mortality. Despite this, highly accurate, sensitive, and non-invasive diagnostic tools are currently not aviailable, yet no FDA approved drugs for MASLD. The advance of proteomics has enable the study of protein expression, post-translational modifications (PTMs), subcellular distribution, and interactions. In this review, we discuss insights gained from the recent proteomics studies that shed new light on the pathogenesis, diagnosis and potential theraputic targets of MASLD.