The amyloid β-protein (Aβ) plays an indispensable role in the pathogenesis of Alzheimer disease (AD). Aβ is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Aβ-degrading proteases (AβDPs). A growing number of AβDPs have been identified that impact Aβ powerfully and in a surprising variety of ways. As such, AβDPs hold considerable therapeutic potential for the treatment and/or prevention of AD. Here, we critically review the relative merits of therapeutic strategies targeting AβDPs compared with current Aβ-lowering strategies focused on immunotherapies and pharmacological modulation of Aβ-producing enzymes. Several innovative advances have increased considerably the feasibility of delivering AβDPs to the brain or enhancing their activity in a non-invasive manner. We argue that therapies targeting AβDPs offer numerous potential advantages that should be explored through continued research into this promising field.