Recently, Flores-Muñoz et al. [56] using radioligand binding assays observed that Ang-(1-9) is able to bind the Ang II type 2 receptor (AT2R) (pKi = 6.28 ± 0.1). They demonstrated that Ang-(1-9) and not Ang II, affected hypertrophy through the AT2R, as PD123319 (an AT2 receptor blocker) did not alter Ang II-mediated growth but did block the effects of Ang-(1-9). Despite having ∼100fold lower affinity than Ang II for the AT2R [57] , the selective AT2R activity of Ang-(1-9) is not inconsistent with current pharmacological models of G protein-coupled receptor signalling and activation. Indeed, the concept of functional selectivity, where individual receptor ligands have the capacity to selectively stabilize conformations which lead to distinct signalling outcomes [57] [58] [59] , is supported by a previous study in which the critical amino acids and the mode of binding of ligands at the AT1R and AT2R were investigated [60] . While agonist activation of the AT1R was particularly sensitive to peptide modifications that disrupted contact points between Ang II and its receptor, substitutions within Ang II were far better tolerated by the AT2R [60] . The AT2R exists in a relaxed conformation and Ang II therefore binds to multiple indistinct contact points [60] . Since Ang-(1-9) contains the entire Ang II sequence plus a C-terminal histidine, these observations indicate that this difference may stabilize the AT2R in a conformation able to counteract hypertrophic signalling in cardiomyocytes. Flores-Muñoz et al. [56] did not observe functional competition between Ang II and Ang-(1-9) at the AT2R and they concluded that that Ang-(1-9) is able to antagonize Ang II signalling in cardiomyocytes selectively via the AT2R, highlighting that Ang-(1-9), along with Ang-(1-7), makes up part of the counter-regulatory arm of the RAS. What remains to be determined is the downstream signalling effects from Ang- (1) (2) (3) (4) (5) (6) (7) (8) (9) . Preliminary studies indicate that the classical pathways via PKC translocation and ERK1/2 activation [61] [62] [63] are not different between Ang II-, Ang-(1-7)-and Ang-(1-9) stimulated cells. Since the downstream signalling from the AT2R is unclear at present, future studies will be required to establish these mechanisms.