Alzheimer’s disease (AD) is the most common form of dementia, affecting tens of millions worldwide, yet the few approved therapeutics are modestly effective at best. Pathological features include cerebral plaques composed of amyloid β-peptide (Aβ), neurofibrillary tangles composed of the microtubule-associated protein tau, and neuroinflammation due to activation of glial cells. Rare inherited cases of early-onset AD are caused by mutations in the substrate and enzyme that produce Aβ, and these mutations alter the production or properties of Aβ to increase the propensity for plaque deposition. These discoveries led to the formulation and ostensible confirmation of the amyloid cascade hypothesis that has dominated AD research and drug discovery for over three decades. This chapter provides an overview of AD biology and approved medications, leading ideas on mechanisms of pathogenesis, key drug targets based on these mechanisms, and an assessment of the current pipeline for small-molecule therapeutics. Challenges to AD drug discovery are also presented, most notably uncertainty regarding pathogenic mechanisms and whether current targets are appropriate. Dominance of the amyloid hypothesis may be holding back the field, but artificial intelligence may help break the logjam in developing more effective therapeutics for prevention and treatment.