In fatty acid oxidation defects, the majority of gene variations are of the missense type and, therefore, prone to inducing misfolding in the resulting mutant protein. The fate of the mutant protein depends on the nature of the gene variation and other genetic factors as well as cellular and environmental factors. Since it has been shown that certain fatty acid oxidation enzyme proteins, exemplified by mutant medium-chain and short-chain acyl-CoA dehydrogenases as well as electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase, may accumulate during cellular stress, e.g. elevated temperature, there is speculation about how such proteins may disturb the integrity of the putative fatty acid oxidation metabolone, in which the two flavoproteins link the matrix-located acyl-CoA dehydrogenases to the respiratory chain in the mitochondrial inner membrane. However, since studies so far have not been able to define the fatty acid oxidation metabolone, it is concluded that new concepts and refined techniques are required to answer these questions and thereby contribute to the elucidation of the cellular pathophysiology and the genotype-phenotype relationship in fatty acid oxidation defects.