G-protein-coupled receptors (GPCRs) transmit extracellular signals across the plasma membrane via intracellular activation of heterotrimeric G proteins. The signal transduction pathways of Gs, Gi and Gq protein families are widely studied, whereas signaling properties of G12 proteins are only emerging. Many GPCRs were found to couple to G12/13 proteins in addition to coupling to one or more other types of G proteins. G12/13 proteins couple GPCRs to activation of the small monomeric GTPase RhoA. Activation of RhoA modulates various downstream effector systems relevant to diseases such as hypertension, artherosclerosis, asthma and cancer. GPCR screening assays exist for Gs-, Gi- and Gq-linked pathways, whereas a drug-screening assay for the G12-Rho pathway was developed only recently. The review gives an overview of the present understanding of the G12/13-related biology of GPCRs.