Modulation of cell signaling by ligands of different efficacies via G-protein coupled receptors (GPCRs), depends intrinsically on the effect of the ligand on the dynamics between the multiple conformational states of these proteins. Ligands with different efficacies can remodel the energy landscape of the receptors, thereby perturbing this conformational equilibrium in many ways depending on the nature of the ligand, and the G-proteins that the receptor couples to, thereby conferring functional specificity. Understanding activation dynamics and pathways is vital in designing functionally specific drugs for GPCRs.Starting from the crystal structure of beta2-adrenergic receptor (B2AR), we have used LITiCon computational method to predict the ligand stabilized receptor state with full (epinephrine and norepinephrine), partial (salbutamol and dopamine), and inverse agonists (carazolol) bound. We have calculated the minimum energy pathway going from the inactive to the ligand stabilized state for each of the ligand/receptor complex. The activation pathways derived for all the agonists studied here are in agreement with fluorescence lifetime measurements1,2. We have also studied the norepinephrine activation pathway for the mutant m23 avian beta1-adrenergic receptor (B1AR) that has been crystallized, and the wild type B1AR. We show that the activation barrier for activation of the mutant m23B1AR by norepinephrine, is larger than for the wildtype B1AR, which is in agreement with the previous experimental finding that m23B1AR requires higher concentration of norepinephrine for activation3.Virtual ligand screening with the salbutamol-stabilized B2AR conformation shows enrichment of non-catechol agonists over norepinephrine-stabilized conformation. Our computational method provides an unprecedented opportunity to understand activation mechanisms in GPCRs.1. Swaminath G, et al. (2004), J. Biol. Chem. 279:686-691.2. Swaminath G, et al. (2005) , J. Biol. Chem. 280:22165-22171.3. Warne T., et. Al., (2008), Nature, 454, 486-491.