The molecular determinants of Alzheimer's (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca(2+)) and zinc (Zn(2+)). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-β dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca(2+) and Zn(2+) dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca(2+) and Zn(2+) rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca(2+) and Zn(2+) dyshomeostasis may offer a great opportunity for disease-modifying strategies.