Numerous studies have documented the involvement of p130Cas (Crk-associated substrate) in a wide range of cellular processes across different types of cells. These processes encompass cell transformation, the connection between the extracellular matrix and the actin cytoskeleton, cell migration and invasion, and cardiovascular development. Moreover, p130Cas has been associated with the regulation of various physiological processes, including mammary, bone, brain, muscle, and liver homeostasis. The diverse functions of p130Cas can be attributed to its possession of multiple protein-protein interaction domains, which sets it apart as a unique class of adaptor protein. It is well established that p130Cas interacts critically with the CT10 regulator of kinase (Crk) adaptor protein family members, including CrkII, CrkI, and Crk-like (CrkL), which is the basis for the naming of the Cas family. The Crk family proteins play a crucial role in integrating signals from various sources, such as growth factors, extracellular matrix molecules, bacterial pathogens, and apoptotic cells. An increasing body of evidence suggests that the dysregulation of Crk family proteins is linked to various human diseases, including cancer and increased susceptibility to pathogen infections. This review focuses primarily on the structural and functional aspects of the interaction between p130Cas and the Crk family proteins, providing insights into how these proteins regulate specific signaling events. Furthermore, we delve into the functions of p130Cas and the Crk family proteins in both normal and tumor cells to gain a comprehensive understanding of their collaborative roles in cellular physiology and pathology. This review demonstrates that tumor cell migration and invasion are the two cellular functions that have been studied the most for the p130Cas-Crk/CrkL axis. Understanding the tumor cell migration and invasion that require both p130Cas and Crk/CrkL is necessary to further evaluate the role of the p130Cas-Crk/CrkL axis in cancer. Establishing the contribution of the p130Cas-Crk/CrkL axis to cancer will facilitate the development of cancer drugs targeting the axis to inhibit cancer cell dissemination and improve patient outcomes.