Highly concentrated metals such as Cu, Zn, and Fe are found in amyloid-beta (An) plaques within the brain of Alzheimer's disease (AD). In vitro and in vivo studies have suggested that metal binding to A beta could facilitate A beta aggregation and generate reactive oxygen species (ROS), which could contribute to the neuropathogenesis of AD. The connection between metal-A beta interaction/reactivity and AD development, however, has not been clearly revealed owing to the complexity of the disease. In this review, metal-A beta interaction/reactivity and its relation to neurotoxicity are briefly discussed. Additionally, our review illustrates the recent progress of small molecules, capable of targeting metal-A beta species and modulating their interaction/reactivity, which could offer a promising approach to interrogate their role in AD.