Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TRβ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TRα appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TRβ activation on metabolic rate and HR with either TRα₁^–/– mice or the selective TRβ agonist KB-141 in mice, rats, and monkeys. 3,5,3′-triiodi-l-thyronine (T₃) had a greater effect on increasing HR in WT than in TRα^–/– mice (ED₁₅ values of 34 and 469 nmol/kg/day, respectively). T₃ increased metabolic rate [whole body oxygen consumption (MV_O2)] in both WT and TRα^–/– mice, but the effect in the TRα₁^–/– mice at the highest dose was half that of the WT mice. Thus, stimulation of MV_O2 is likely due to both TRα and -β. T₃ had equivalent potency for cholesterol reduction in WT and TRα^–/– mice. KB-141 increased MV_O2 with selectivities of 16.5- and 11.2-fold vs. HR in WT and TRα₁^–/– mice, respectively. KB-141 also increased MV_O2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TRβ-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).