G-protein coupled receptors (GPCRs), a major gatekeeper of extracellular signals on plasma membrane, are unarguably one of the most important therapeutic targets. Given the recent discoveries of allosteric modulations, an allosteric wiring diagram of intramolecular signal transductions would be of great use to glean the mechanism of receptor regulation. Here, by evaluating betweenness centrality (CB) of each residue, we calculate maps of information flow in GPCRs and identify key residues for signal transductions and their pathways. Compared with preexisting approaches, the allosteric hotspots that our CB-based analysis detects for A2A adenosine receptor (A2AAR) and bovine rhodopsin are better correlated with biochemical data. In particular, our analysis outperforms other methods in locating the rotameric microswitches, which are generally deemed critical for mediating orthosteric signaling in class A GPCRs. For A2AAR, the inter-residue cross-correlation map, calculated using equilibrium structural ensemble from molecular dynamics simulations, reveals that strong signals of long-range transmembrane communications exist only in the agonist-bound state. A seemingly subtle variation in structure, found in different GPCR subtypes or imparted by agonist bindings or a point mutation at an allosteric site, can lead to a drastic difference in the map of signaling pathways and protein activity. The signaling map of GPCRs provides valuable insights into allosteric modulations as well as reliable identifications of orthosteric signaling pathways. Proteins 2014; 82:727–743. © 2013 Wiley Periodicals, Inc.