It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features including 1) [Ca²⁺]_i, contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types such as epithelium, fibroblasts and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening and fibrosis that influences compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard, and helps set the stage for future research towards understanding the pathways regulating ASM, and in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, COPD and pulmonary fibrosis.