Amyloid β (Aβ) plaque, comprised mainly by Aβ peptides, is an important pathology of Alzheimer's brains. Major efforts have been devoted to targeting this neurotoxic Aβ peptide for discovering disease-modifying treatments for Alzheimer's disease. Inasmuch as Aβ is found in both the brain and the periphery, it is hypothesized that there is some form of equilibrium for the Aβ in the brain and the periphery such that Aβ can be transported across the blood-brain barrier. By modulating the periphery Aβ levels, it is predicted that the brain Aβ levels will undergo concomitant changes, forming the basis of the "sink hypothesis" for Aβ lowering strategies. In this review, the significance and implication of this sink hypothesis as well as how the sink hypothesis may contribute to the recent Aβ-based drug discovery in AD are discussed. Ultimately, the validity of the sink hypothesis will be resolved when the appropriate Aβ agents are being tested in the clinic.