Simple SummaryCancer is a leading cause of death worldwide, with most of these deaths being the result of tumor metastasis (spread of cancer cells from the primary site). The sterile alpha motif (SAM) domain is a crucial protein module that can regulate many interactions among proteins, including those important for cancer development or metastasis. This review explores the literature on a group of under-studied proteins that contain multiple SAM domains. Our focus will be on these proteins, with a particular emphasis on the latest findings regarding the structural dynamics and interaction arrangements present within their SAM domains. We will also discuss the similarities as well as the uniqueness of their effects, functions, and regulations. We aim to provide a better understanding of these SAM domains and these proteins, which may offer clues to develop novel anticancer drugs.AbstractSAM domains are crucial mediators of diverse interactions, including those important for tumorigenesis or metastasis of cancers, and thus SAM domains can be attractive targets for developing cancer therapies. This review aims to explore the literature, especially on the recent findings of the structural dynamics, regulation, and functions of SAM domains in proteins containing more than one SAM (multi-SAM containing proteins, MSCPs). The topics here include how intrinsic disorder of some SAMs and an additional SAM domain in MSCPs increase the complexity of their interactions and oligomerization arrangements. Many similarities exist among these MSCPs, including their effects on cancer cell adhesion, migration, and metastasis. In addition, they are all involved in some types of receptor-mediated signaling and neurology-related functions or diseases, although the specific receptors and functions vary. This review also provides a simple outline of methods for studying protein domains, which may help non-structural biologists to reach out and build new collaborations to study their favorite protein domains/regions. Overall, this review aims to provide representative examples of various scenarios that may provide clues to better understand the roles of SAM domains and MSCPs in cancer in general.