Rodents exposed to the environmental contaminant, TCDD, suffer from a number of acute and chronic toxicities, including lethality and a wasting syndrome. Hypothesizing that the wasting syndrome may be caused by changes in neural control of energy flux and metabolism, we profiled the transcriptional response of rat hypothalamus to TCDD. We employed two separate rat strains: the Long-Evans strain is sensitive to TCDD toxicities while the Han/Wistar strain is over four orders of magnitude more resistant. Surprisingly, few transcriptional changes were induced by TCDD in either strain. Only four genes were altered in Long-Evans rats, including three classic TCDD-responsive genes: Cyp1a1, Cyp1b1, and Nqo1. These three genes were also altered in Han/Wistar rats, along with 133 additional genes. However, the magnitudes of alteration of these additional genes was very modest, with most changes well below two-fold in magnitude. We therefore concluded that rat hypothalamus is mostly refractory to TCDD exposure, at least at the doses and time-points surveyed here.