The Hedgehog (Hh) signalling pathway is highly conserved and has a role in many cellular processes involved in development and disease. Hh binding to its receptor Patch (Ptc) alleviates Ptc repression of Smoothend (Smo), the key signal transductor of the Hh pathway. This leads to the redistribution of Smo to the plasma membrane, phosphorylation of its cytoplasmic tail, Smo oligomerisation and, subsequently, activation of the pathway. However, a number of questions remain with regard to the spatial and temporal regulation of these events. In this study (p. 4684), Christian Bökel and co-workers use mathematical modelling and visualisation of the phosphorylation status of Smo together with a conformation-sensitive fluorescence-based reporter to investigate the molecular events downstream of Smo phosphorylation. They find that that localization of Smo to the plasma membrane is sufficient to induce phosphorylation of its cytoplasmic tail, both in the presence and absence of Ptc. Moreover, the authors demonstrate that the inactivation of Ptc in response to Hh controls Smo clustering at the plasma membrane independently of the phosphorylation of the Smo tail. This result is surprising because Smo phosphorylation has been proposed to be required for its membrane clustering. The data presented here, therefore, support a model of Hh pathway activation, in which the inhibitory role of Ptc is primarily mediated by influencin the subcellular localization of Smo.