Hormones that act through nuclear receptors contribute to vertebrate development and homeostasis by serving as biological signals to control cellular growth and differentiation. Their response pathways must meet two requirements, which can be contradictory: they must be highly specific for a given signal, but at the same time they have to be flexible, allowing different responses under different physiological conditions. The current model for nuclear signalling of vitamin D3 (calcitriol), thyroid hormone and retinoic acid seems to be too simple to solve the specificity puzzle. Therefore, an advanced model is proposed that combines recent findings on the structure of hormone response elements, the promiscuous dimerization of the receptors for vitamin D3, thyroid hormone and retinoids and the heterodimer polarity. Special attention is taken on the mechanism of vitamin D3 signalling, where at least 14 different pathways are differentiated.