The endocytic pathway is involved in activation and inhibition of cellular signaling. Thus, defining the regulatory mechanisms that link endocytosis and cellular signaling is of interest. An emerging link between these processes is a family of proteins called intersectins (ITSNs). These multidomain proteins serve as scaffolds in the assembly of endocytic vesicles and also regulate components of various signaling pathways, including kinases, guanosine triphosphatases, and ubiquitin ligases. This review summarizes research on the role of ITSNs in regulating both endocytic and signal transduction pathways, discusses the link between ITSNs and human disease, and highlights future directions in the study of ITSNs.