The endothelin (ET) system is altered in cardiovascular diseases and ET receptor antagonists are licenced for treatment of pulmonary arterial hypertension (PAH). Endothelins act via two G-protein-coupled receptors (GPCRs), ETA and ETB. However, it is recognised that GPCRs may also activate signalling pathways in a G-protein-independent manner via beta-arrestin. Ligand-specific pathway modulation (biassed agonism/antagonism) may have therapeutic application and therefore we have investigated the potential for pathway bias of ET agonists and antagonists. Concentration-response curves were constructed to ET agonists using ETA and ETB beta-arrestin assays. ET receptor antagonists were tested for their ability to block ET-1 responses in each assay and agonist-dependence of the ETA selective antagonist BQ123 was investigated. These data were compared to results from binding experiments in human heart (that expresses both subtypes) and to ETA-mediated vasoconstrictor experiments in human saphenous vein. The relative potency of ET peptides in the ETA and ETB beta-arrestin assays was as expected. Interestingly, for ETA, compared to ET-1, all other agonists tested were partial agonists. Differences from the known pharmacology of antagonists were also revealed in the beta-arrestin assays. Specifically, BQ123 behaved as a negative allosteric modulator in the ETA assay, exhibiting agonist-dependent affinities. Bosentan was a potent ETA-selective antagonist in the beta-arrestin assay in contrast to its non-selective profile determined in human heart. The apparent ETA beta-arrestin bias of bosentan may contribute to its clinical effectiveness in PAH but further investigation of a role for functional selectivity and biassed signalling via the ET receptors in cardiovascular disease is required.