The regulated intramembrane proteolysis (RIP) of APP, consisting of the sequential action of a- or ß-secretases and presenilin-?-secretase, generates three protein fragments: an APP ectodomain, the APP intracellular domain (AICD) and several small peptides, including the amyloid ß (Aß). The latter has been attributed with an initiating role in the neuropathological changes that underlie Alzheimer's disease (AD). However, the therapeutic strategies targeting Aß have been largely ineffective in the disease treatment, suggesting that another peptide could be involved, like AICD. Additionally, the physiological functions of the APP itself remain obscure, although they may be related to the RIP, an evolutionarily conserved mechanism that allows several transmembrane receptors to signal to the nucleus. In the RIP, the major peptide involved in signalling corresponds to the intracellular domain of the transmembrane protein. Despite its small size, the AICD can form several multiprotein complexes, which not only controls Aß production, but have also been associated with the regulation of neurogenesis, cytoskeletal dynamics, response to DNA damage, cell cycle control, among others. Reinforcing the physiological importance of the AICD in the biology of APP, multiple phosphorylation events reshaping the AICD interactome and regulating its downstream effects. In this chapter we will present recent evidence from cellular and animal models, strongly suggesting that the AICD and its interacting proteins could play an unprecedented role on physiological functions of APP, and that its deregulation has a profound impact in the initiation of AD, and therefore opening new therapeutic avenues for treating this devastating disease.