Besides of their role as important energy source and membrane component, long chain fatty acids also act as bioactive lipids involved in the regulation of such processes like cell proliferation and differentiation, protein acylation and sorting, inflammation, activation of enzymes and membrane receptors, and regulation of intracellular metabolism. One of the mechanisms by which fatty acids affect so many various biological processes is regulation of the gene transcription. Depending on the number of double bonds and carbon chain length, fatty acids may inhibit or activate expression of defined genes through either direct regulation of activity of nuclear receptors including PPAR, LXR and HNF-4 alpha or transcription factors mainly SREBP, ChREBP and NF kappa B; or indirectly, through physicochemical changes in membrane properties and activation of signal transduction pathways. In this paper we review the current understanding of the mechanisms by which fatty acids regulate gene expression and discuss their role in the pathogenesis of metabolic disorders.