For more than 15 decades, airway smooth muscles (ASMs) contraction has been recognized as the primary driving mechanism for asthma attacks. Breathing has a strong relaxing and protection effect on ASM by inhibiting airway constriction. It is crucial to understand the behavior of ASM, which helps to understand the reversible airway obstruction associated with asthma. Many authors worldwide, including our group, have conducted intensive research on computational modeling of ASMs in an attempt to understand their behaviors and responses. However, after about 25 years of work in this field, nothing can replace the need for real-life experimental programs to understand physiological systems and their elements, in particular cells such as ASM. In any physiological system, including a small cell, it is not possible to have a complete model which can address the effects of all active and passive components in the system. Obviously, there are many physiological, physical, and environmental triggering mechanisms that make it impossible to duplicate all real-life activities in a mathematical or computational model. In brief, nothing will replace the experimental and laboratory studies on a cell such as a smooth muscle. Therefore, this chapter focuses on experimental investigations, which are summarized in the rest of the chapter.