Focal adhesion plaques (FAPs) are multi-protein aggregates，which act as physical connections between extracellular matrix and cytoskeleton (CSK). FAPs and CSK play important roles in the conversion of mechanical signals into intracellular chemical signals followed by physiological and pathological responses. With focus on FAPs-CSK system, this review summarized the process of fluid shear stress-induced mechanotransduction and the roles of FAPs and CSK in this process in detail, introduced important proteins in FAPs, discussed the relationship between FAPs and other mechanotransduction pathways. The review established the theoretical foundation for understanding of the relationship between fluid shear stress and shear stress-related diseases, as well as development of clinical drug and treatment of these diseases.