Choosing a partner G protein–coupled receptors (GPCRs) bind ligands outside the cell and trigger events inside the cell by selectively binding and activating specific G proteins. The selectivity occurs even among highly related GPCRs. For example, five subtypes of muscarinic acetylcholine receptors (M1R to M5R) play different roles in the nervous system by binding to different G proteins. Maeda et al. determined cryo–electron microscopy structures of M1R and M2R bound to their respective G proteins. A side-by-side comparison provided a molecular understanding of G protein–coupling selectivity. Science , this issue p. 552