Background: Intracellular lipid-binding proteins stimulate lipid-induced gene expression. Results: Fatty acid-binding protein 5 (FABP5) uses a molecular switch that controls nuclear import when complexed with activating fatty acids. Conclusion: FABP5 is tuned to selectively stimulate peroxisome proliferation-activated receptor ␤/␦ transactivation in response to specific fatty acids based on their structural features. Significance: FABPs provide a second level of regulatory control of nuclear receptor-mediated lipid signaling.