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In many tissues, fatty acid binding protein (FABP) expression is stimulated by exposure to elevated fatty acid levels. In contrast to the FABP genes expressed in other tissues, the molecular mechanisms that mediate the upregulation of the muscle FABP gene have not been elucidated. We have studied the expression of locust flight muscle FABP, a protein that is highly homologous to the mammalian H-FABPs. A 130-bp promoter fragment of the locust gene, which includes a canonical TATA box and several GC boxes, is sufficient for the transcription of a reporter gene in mammalian L6 myoblasts. Twofold higher expression rates are observed when the promoter contains 280 bp or more of upstream sequence. Treatment of myoblasts with various fatty acids leads to a marked increase of expression in the longer constructs, but not in the minimal promoter. We have identified a 19-bp inverted repeat (-162/-180) as the element responsible for the fatty acid-mediated induction of gene expression. Deletion of this element eliminates the fatty acid response, and gel shift analysis demonstrates specific binding to nuclear proteins from both L6 myoblasts and locust flight muscle cells. This fatty acid response element bears no similarity to any known transcription factor binding site. A similar palindrome was also found in the promoter of the Drosophila melanogaster muscle FABP gene, and in reverse orientation upstream of all mammalian heart FABP genes. Given the structural and functional conservation of muscle FABPs and their genes, it is possible that this fatty acid response element also modulates the expression of the mammalian H-FABP genes.