Three subhepatocellular compartments concur for fatty acids degradation including ω-oxidation in endoplasmic reticulum and β-oxidation in both mitochondria and peroxisomes. Deficits affecting the peroxisomal physiology may be associated with multiple metabolic disturbances. Nowadays, a growing body of evidence underlines the key role of peroxisomal β-oxidation in the sensing of lipid metabolism through the production/degradation of some essential metabolites. Lessons from several mice models strengthen the link between fatty acid β-oxidation in peroxisomes and the nuclear hormone receptor Peroxisome Proliferator-Activated Receptor (PPAR)-α with an additional level of coregualtor complexity, which couples regulation of body energetic balance and hepatic caloric flux to functional peroxisome status. Here, we review key determinants of disrupted peroxisomal β-oxidation pathway, which in liver promotes hepatic steatosis and hepatocarcinogenesis.