Nuclear receptors (NRs) are transcription factors involved in metabolic control whose activities are, directly or indirectly, modulated by lipophilic molecules. Controlling NRs activities is a valuable therapeutic strategy in treating diabetes and other metabolic diseases. Detailed understanding of NRs mechanisms of action will improve our ability to manipulate their activities with synthetic ligands and to circumvent side effects observed with molecules currently used in therapeutics, and will allow to identify novel therapeutic targets. NRs regulate transcription through a sequential process relying on surface recognition between multiple cofactors, initiated upon ligand docking into the receptor, followed by chromatin structure alteration and general transcription factor recruitment to the promoter of target genes. These molecular events have been detailed for a few in vitro model systems. However, critical steps and components of the activation process are still unknown for many NRs in a pathological context. Our research will address two questions: (i) Can we reach a level of mechanistic knowledge allowing for the definition of reliable structure-activity relationships for NR ligands? (ii) Can we identify and characterize novel components of the NR signalling pathway involved in metabolic diseases? These investigations will therefore on the one hand, unravel novel regulation pathways, and on the other hand, use molecular data to exploit NRs as druggable targets.