Vascular smooth muscle is a key effector in the wall of blood vessels during the pathogenesis of hypertension. Various factors directly elicit smooth muscle cell contraction, migration, growth, and hypertrophy, which lead to the progression of hypertension. Crk-associated substrate (CAS), the first discovered member of the adapter protein CAS family, has recently emerged as a critical cellular component that regulates smooth muscle functions. In this review, the molecular structure and protein interactions of the CAS family members are summarized. Evidence for the role of CAS in the regulation of vascular smooth muscle contractility, cell migration, hypertrophy, and growth is presented. Regulation of CAS by novel tyrosine kinases/phosphatases and unique downstream signaling partners of CAS are also discussed. These new findings establish the important role for CAS in regulating vascular smooth muscle functions. The CAS-associated processes may be new biological targets for the development of new treatment of cardiovascular diseases such as hypertension.