Thyroid hormone has long been known for its profound direct effects on the cardiovascular system, but its interactions with the autonomic nervous system controlling cardiac activity still remain enigmatic. Recently, mice heterozygous for a mutant thyroid hormone receptor α1 (TRα1+/m) have been generated and their analysis has provided new insights into the actions of thyroid hormone on the cardiovascular system. The mutant TRα1 caused many symptoms resembling hypothyroidism, such as bradycardia, as well as reduced contraction and delayed relaxation time of isolated cardiomyocytes. While no abnormalities were detected in the autonomic regulation of the basal heart rate using pharmacologic denervation, an impaired adjustment of the autonomic nervous system could be observed in TRα1+/m mice on activity, stress, or increased temperature. The results thus confirm the important role of TRα1 in maintaining the intrinsic properties of the heart and demonstrate a novel role for TRα1 in the adaptations of the autonomic nervous system controlling the heart rate under non-baseline conditions.