There is growing evidence indicating the existence of a causal relationship between abnormal airway smooth muscle (ASM) function and airway hyper-responsiveness, a poorly understood feature of asthma that can be defined as an excessive bronchospastic response. In recent years, there has been a veritable explosion of articles suggesting that ASM exposed to proasthmatic cytokines can elicit a hyper-responsive state to contractile G-protein-coupled receptor (GPCR) agonists. Aberrant airway responsiveness could result from abnormal calcium signaling, with changes occurring at various levels of GPCR-associated signal transduction. This review presents the latest observations describing novel mechanistic models that could explain the involvement of ASM in airway hyper-responsiveness. This review will discuss the role of ASM in β2-agonist-mediated bronchial hyper-responsiveness and the clinical significance of cell–cell contact between ASM and mast cells recently described to be intimately infiltrated within the ASM tissues in asthmatic patients. The possibility that allergens could trigger airway hyper-responsiveness by directly acting on ASM via activation of immunoglobulin E receptors, FcεRI and FCεRII will also be discussed. These important findings further support the notion that targeting ASM could offer new treatment for many features of asthma, including airway hyper-responsiveness. Future therapeutic intervention includes: the prevention of ASM–inflammatory cell physical and/or functional interaction, the inhibition of Immunoglobulin E receptor-dependent signal transduction, and the abrogation of cytokine-dependent pathways that modulate receptor-associated calcium metabolism.