Bronchodilators are used to improve symptoms and lung function in asthma and COPD. Airway smooth muscle tone is regulated by both muscarinic and β2-adrenergic receptor activity. Large-conductance Ca2+-activated K+ (KCa) channels are activated by β2-adrenergic receptor agonists, via Gs, and suppressed by muscarinic receptor antagonists via Gi. This functional antagonism converges on the G protein/KCa channel linkages. Membrane potential regulated by KCa channels contributes to airway smooth muscle tension via Ca2+ influx passing through voltage-dependent Ca2+ (VDC) channels. The Gs/KCa/VDC channel linkage is a key process in not only physiological effects, but also in dysfunction of β2-adrenergic receptors and airway remodeling. Moreover, this pathway is involved in the synergistic effects between β2-adrenergic receptor agonists and muscarinic receptor antagonists. Intrinsic efficacy is also an important characteristic for both maintenance and loss of β2-adrenergic action. Allosteric modulators of G protein-coupled receptors contribute not only to this synergistic effect between β2-adrenergic and muscarinic M2 receptors, but also to intrinsic efficacy. The effects of weak partial agonists are suppressed by lowering receptor number, disordering receptor function, and enhancing functional antagonism; in contrast, those of full or strong partial agonists are not suppressed. Excessive exposure to full agonists causes β2-adrenergic desensitization; in contrast, exposure to partial agonists does not cause desensitization. Intrinsic efficacy may provide the rationale for the clinical use of β2-adrenergic receptor agonists in asthma and COPD. In conclusion, the G protein/KCa linkage and intrinsic efficacy (allosteric effects) may be therapeutic targets for research and development of novel agents against both airway obstruction and airway remodeling.