Nuclear receptors (NRs) are hormone-sensing transcription factors that translate dietary or endocrine signals into changes in gene expression. Therefore, the adoption of orphan NRs through the identification of their endogenous ligands is a key element for our understanding of their biology. In this minireview, we give an update on recent progress in regard to endogenous ligands for a cluster of NRs with high sequence homology, namely peroxisome proliferator-activated receptors α and γ, Rev-erbα, and related receptors. This knowledge about the nature and physiology of these ligands may create new opportunities for therapeutic drug development.