Proper function of the endoplasmic reticulum (ER) and mitochondria is essential for cellular homeostasis and the regulation of metabolic pathways. Perturbation of their function has been linked to pathophysiological states, including metabolic and liver diseases. Fatty liver diseases are a major health problem whose prevalence is dramatically increasing, may be induced by several factors (mainly chronic alcohol consumption, drugs or metabolic alterations), and share common features as lipid deposition, inflammation, oxidative stress and progression to more severe clinical stages, such as fibrosis, cirrhosis or even hepatocellular carcinoma. Besides their independent contributions to metabolic and hepatic pathologies, mitochondria and ER directly interact regulating each other's function, and ER-mitochondria interface is involved in several molecular pathways, as induction of autophagy and triggering of inflammatory cascades. Disturbances in these interactions have already been implicated in different human diseases, and increasing interest is arising in their role on liver illnesses. This review summarizes the current understanding regarding mitochondrial and ER implication in fatty liver diseases, focusing on lipid accumulation and inflammation, and the relevance of both the individual functions of these organelles and of ER-mitochondria interactions in such processes. In addition, it describes the clinical implications and the available therapeutic options targeting directly these organelles or associated molecular mechanisms.