INTRODUCTION: Asthma is a chronic lung disease influenced by environmental and inflammatory triggers and involving complex signaling pathways across resident airway cells such as epithelium, airway smooth muscle, fibroblasts, and immune cells. While our understanding of asthma pathophysiology is continually progressing, there is a growing realization that cellular microdomains play critical roles in mediating signaling relevant to asthma in the context of contractility and remodeling. Mechanosensitive pathways are increasingly recognized as important to microdomain signaling, with Piezo and transient receptor protein (TRP) channels at the plasma membrane considered important for converting mechanical stimuli into cellular behavior. Given their ion channel properties, particularly Ca conduction, a question becomes whether and how mechanosensitive channels contribute to Ca microdomains in airway cells relevant to asthma. AREAS COVERED: Mechanosensitive TRP and Piezo channels regulate key Ca regulatory proteins such as store operated calcium entry (SOCE) involving STIM and Orai channels, and sarcoendoplasmic (SR) mechanisms such as IP receptor channels (IPRs), and SR Ca ATPase (SERCA) that are important in asthma pathophysiology including airway hyperreactivity and remodeling. EXPERT OPINION: Physical and/or functional interactions between Ca regulatory proteins and mechanosensitive channels such as TRP and Piezo can toward understanding asthma pathophysiology and identifying novel therapeutic approaches.