Thyroid hormone receptors (TRs) and liver X receptors (LXRs) are members of the nuclear receptor superfamily. Although LXRs and TRs belong to two distinct receptor subgroups with respect to ligand-binding affinity, the two receptor systems show similarity with respect to molecular mechanism, target genes, and physiological roles. Since both TRs and LXRs play an important role in metabolic regulation, form heterodimers with retinoid X receptors (RXRs), and bind to direct repeat-4 (DR-4) with identical geometry and polarity, crosstalk between these two receptors has been reported, especially on lipid metabolism-related genes. Recently, several types of crosstalk between TRs and LXRs have been identified and crosstalk has also been observed in other physiological systems such as central nervous system rather than lipid metabolism. In this review, recent advances in elucidating the molecular mechanisms of the crosstalk between these two nuclear receptors are discussed, with the aim of finding a perspective on unknown roles of TRs and LXRs.