Only a decade ago, the attempt to develop therapeutic agents for the effective long-term treatment and cure of neurodegenerative disorders such as Alzheimer's disease (AD) might have been likened to attacking a windmill with a lance, as answers to key questions about biochemical processes, target proteins, models, and clinical assessment were unclear. By the close of the century, molecular events underlying major neurodegenerative diseases were unraveling, laying the foundation for pharmaceutical intervention. AD pathology involves extraneuronal plaques (major component amyloid-β protein, Aβ) and intraneuronal tangles (tau protein). Genetic studies identified causative genes (APP, presenilins 1/2) and a risk factor (apoE4), all linked to increased Aβ production—particularly the fibrillogenic Aβ42. The amyloid hypothesis states that Aβ production and deposition lead to neuronal death and AD progression. Reducing Aβ production is a key therapeutic strategy, with the proteases (α-, β-, γ-secretases) cleaving Aβ from its precursor APP emerging as top targets. β-Secretase (BACE), a membrane-bound aspartyl protease, was recently identified via multiple approaches. This Perspective discusses the biology of these integral membrane proteases and their substrates, current pharmacological approaches to modulating their actions, and assesses the potential of these targets for AD treatment.