The saga of nuclear receptor started in the early part of the last century based on the ability of steroid and thyroid hormones, and of Vitamin D3, to impact development, metamorphosis, cell differentiation, and physiology, but the mediators of their action remained elusive for a long time. The development of radiolabelled ligands allowed the identification of binding proteins that were shown to translocate to the nucleus, indicating a link between transcriptional regulation and physiology. They were shown to be targeted to responsive tissues by specific high affinity receptor proteins more than 50 years ago. The subsequent identification of genes responsive to these hormones completed the initial characterisation of a steroid hormone signalling pathway. The cloning of the fist steroid receptors in the mid-1980 was a key step towards understanding the molecular and cellular mechanisms underlying signalling pathways controlled by these hormones and the identification of the various members of the nuclear receptor superfamily. The laboratory of Pr. Pierre Chambon in Strasbourg made major contributions in the field. Indeed, the cloning of the human oestrogen receptor was reported in 1985, and followed by extensive structure-function analyses that identified and characterised the various domains of the protein. The information gained from these studies allowed to subsequently clone the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Their expression patterns were extensively characterised. Thanks to the development of knockout mice in the late 80’, comprehensive genetic analyses of these receptors, including single and compound mutant mouse lines were performed. As various combinations of RXR/RAR mutations synergistically recapitulated most defects seen in RAR double mutants, strong genetic evidence was provided that RXR/RAR heterodimers are functional in transducing the retinoid signal in vivo. Moreover, thanks to a collaboration with the laboratory of Dr. Dino Moras, the liganded RAR and unliganded RXR LBD 3D structures were resolved. Comparison of these structures revealed that RA binding to a predominantly hydrophobic pocket was ‘sealed-in’ by the folding over of the C-terminal helix H12, referred to as a ‘mousetrap mechanism’. In addition, the development of spatio-temporally controlled targeted mutagenesis based on the CreERT2/LoxP system, allowed to determine the cell-specific function of various nuclear receptors and generate mouse models of human diseases. Vitamin D receptor structural and functional analyses were initiated in Strasbourg 25 years ago and are still actively ongoing. Key steps of this exciting journey will be presented.