Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a 3-methyl branched-chain fatty acid (FA), which accumulates in tissues and body fluids of Refsum patients. 3-Methyl FAs like phytanic acid, first need to undergo alpha-oxidation to produce the corresponding 2-methyl FA plus CO2. In contrast to 3-methyl FAs, 2-methyl FAs like pristanic acid (2,6,10,14-tetramethylpentadecanoic acid), the product of phytanic acid alpha-oxidation, can be beta-oxidized. The mechanism of alpha-oxidation has been resolved in recent years and involves 4 reactions, including: (1.) activation of phytanic acid to phytanoyl-CoA; (2.) 2-hydroxylation of phytanoyl-CoA; (3.) cleavage of 2-hydroxyphytanoyl-CoA to formyl-CoA and pristanal, and (4.) oxidation of pristanal to pristanic acid. The enzymology of the alpha-oxidation pathway has been worked out in some detail, especially for phytanoyl-CoA hydroxylase and 2-hydroxyphytanoyl-CoA lyase, catalyzing the second and third step of alpha-oxidation. Both enzymes are localized in peroxisomes, which explains why alpha-oxidation is strictly peroxisomal. In most patients suffering from Refsum disease (RD) phytanoyl-CoA hydroxylase is deficient, due to mutations in the structural gene (PHYH/PAHX). In search for an alternative therapy for RD we have recently focused on an alternative mechanism for phytanic acid degradation, i.e. omega-oxidation, and have found that the first step in the omega-oxidation pathway is catalyzed by different CYP450s, notably 4F3A, 4F3B, 4A11, and 4F2, in decreasing order of catalytic efficiency. Future studies are aimed at the identification of compounds able to induce the expression of the different CYP450s, in order to increase the capacity to omega-oxidize phytanic acid and thereby lower phytanic acid in RD patients. We will first test candidate compounds like fibrates, which are able to upregulate CYP4A11 expression in a mouse model for RD, which we have generated recently.