The Small Heterodimer Partner (SHP) is an orphan nuclear receptor and an atypical member of the nuclear receptor superfamily Since its discovery, a growing body of evidences have pointed out a pivotal role for SHP in the transcriptional regulation of a variety of target genes involved in diverse metabolic pathways. While we have previously developed a homology model of the structure of SHP that was instrumental to identify a putative ligand binding pocket and suggest the possibility of the development of synthetic modulators, others reported that some atypical retinoids may represent the first synthetic ligands for this receptor. In this work, we report a combined computational approach aimed at shedding further lights on the binding mode and mechanism of action of some atypical retinoids as ligands of SHP. The results have been instrumental to design mutagenesis experiments whose preliminary data suggest the presence of a functional site in SHP as defined by residues Phe96, Arg138 and Arg238. While further experimental studies are ongoing, these findings constitute the basis for the design and identification of novel synthetic modulators of SHP functions.