Nuclear receptors are ligand-regulated transcription factors that evolved from an ancestral orphan receptor into a highly diverse family present throughout the entire animal kingdom. They encompass receptors for steroid and non-steroid hormones, vitamins and metabolic intermediates. These receptors signal through endocrine, paracrine, autocrine and intracrine networks to regulate multiple aspects of animal physiology, including homeostasis, development and reproduction. They exert genomic effects via direct binding as monomers, homo- or heterodimers on cognate DNA elements (hormone response elements). They also participate in signal transduction cross-talk to indirectly modulate other gene expression programmes. By coordinating expression of genetic programmes, nuclear receptors contribute to cell fate-determining processes, thereby shaping and sustaining the organism. All these actions result from one fundamental interaction: receptor binding of a cognate ligand, which induces a major allosteric change in the ligand-binding domain. This conformational alteration is transformed into cascades of protein-protein recognitions, culminating in the establishment of coregulator/cointegrator complexes on gene promoters. Coregulators induce chromatin remodelling and acetylation, thus enabling the targeted recruitment and activation of the basal transcription machinery. This review discusses the molecular infrastructure of nuclear receptor signalling. Emphasis is given to determinants of signalling specificity, especially since they highlight prominent targets for novel drug discovery.