Exploring a range of signaling Cytokines are small proteins that bind to the extracellular domains of transmembrane receptors to activate signaling pathways inside the cell. They often act by dimerizing their receptors, and changes in dimer orientation of the extracellular domains can change the signaling output. Mohan et al. systematically explored this tuning effect by designing a series of dimer ligands for the erythropoietin receptor in which they varied the distance and angle between monomers. The topology affected the strength of activation and differentially affected different pathways, which raises the potential for exploiting such ligands in medicinal chemistry. Science , this issue p. eaav7532