`Physiological relevance' is essential in research into intracellular signalling. Nevertheless, much of our understanding of signalling has been gleaned from studies in 2D cell cultures or in vitro rather than in 3D contexts that mimic the situation in vivo. In a Commentary on p. 2377, Karen Schmeichel and Mina Bissell discuss the range of 3D model systems that now allow examination of how the 3D environment affects how cells perceive and interpret extracellular signals. These range from monotypic 3D cultures in which cells are embedded in laminin-rich reconstituted basement membrane, which have underscored the importance of the extracellular matrix in control of differentiation, to xenograft in vivo models. The latter are highlighting the importance of the stroma in control of organ function, showing, for example, that it is necessary for elaboration of mammary structure and plays an important role in promoting tumour development. Schmeichel and Bissell suggest that these models have immense potential for assessment of potential therapeutic agents but conclude that ultimate physiological relevance will be achieved only once we can model not just tissues but entire organs in vivo.