The effects of cortisol (0.1 mg per dose, administered intraperitoneally to fetal rabbits at 24 to 27 days' gestation), thyrotropin-releasing hormone (40 micrograms/kg per dose administered intravenously to the doe at 24 to 26 days' gestation), or a combination of the two on surfactant pool size (both intracellular and extracellular) at 27 or 28 days' gestation was investigated. Cortisol increased both surfactant pools only when administered on the twenty-fourth or twenty-fifth gestational day. Thyrotropin-releasing hormone, whether administered in single or multiple doses, had no effect on the extracellular pool but increased the intracellular pool; the magnitude of the response (approximately twofold) was similar to that observed with the cortisol response. All combinations of cortisol and thyrotropin-releasing hormone resulted in an increased response over either drug given alone. The greatest response (almost tenfold) resulted from cortisol administration at 24 days' gestation plus thyrotropin-releasing hormone administration at 24+ 25+ 26 days. These data demonstrate differential effects of glucocorticoids and thyrotropin-releasing hormone on developing lung and furthermore show that the timing of their combined treatment may be crucial to achieving maximal response.