In recent years, insights into the mechanisms underlying the biological effects of fatty acids have improved considerably and have provided the foundation for the emerging concept of fatty acid sensing. Fatty acid sensing can be interpreted as the property of fatty acids to influence biological processes by serving as signalling molecules. An important mechanism of fatty acid sensing is via stimulation of DNA transcription via activation of peroxisome proliferators-activated receptors (PPARs) α, β/δ and γ. Apart from fatty acids and various other lipid species, the PPARα subtype is activated by a class of chemicals referred to as peroxisome proliferators. One of the tissues that expresses high levels of PPARα is the liver. Studies in mice have shown that PPARα serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARα suppresses inflammation and the acute phase response. Comparatively little is known about PPARα in human liver. Here I will cover the role and regulation of PPARα in human liver. The main outcomes are: 1) the level of PPARA mRNA expression in human and mouse liver is similar. 2) Expression of PPARA in human liver is reduced in patients with non-alcoholic steatohepatitis or infected with the hepatitis C virus. 3) PPARα in human liver is able to effectively induce the expression of numerous genes involved in numerous lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial fatty acid oxidation, fatty acid binding and activation, fatty acid elongation and desaturation, synthesis and breakdown of triglycerides and lipid droplets, lipoprotein metabolism, gluconeogenesis, bile acid metabolism, and various other metabolic pathways and genes. 4) PPARα activation in human liver causes the down-regulation of a large number of genes involved in various immunity-related pathways. 5) Peroxisome proliferators do not promote tumour formation in human liver as opposed to mouse liver because of structural and functional differences between human and mouse PPARα. 6) In addition to helping to correct dyslipidemia, PPARα agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes. In addition, the functional implications of PPARα activation of specific target genes will be discussed, focusing on the role of PPARα in the regulation of lipid droplets. Lipid droplets can be found in nearly all cell types and may expand during certain (patho)physiological conditions. The synthesis and breakdown of triglycerides and their deposition in lipid droplets is governed by a diverse set of enzymes and lipid droplet-associated proteins. These proteins serve structural roles in and around lipid droplets and regulate the activity of key lipogenic and lipolytic enzymes. Many lipid droplet-associated proteins, including members of the PLIN family, CIDEC, CIDEA, HILPDA, FITM1, FITM2, and G0S2 are under direct transcriptional control of PPARs. Upregulation of lipid droplet-associated proteins by PPARs provides a mechanism to link uptake of lipids to regulation of lipid storage capacity.