The enzyme acetylcholinesterase (AChE) is a key therapeutic target for diseases with cholinergic deficits, such as Alzheimer's disease (AD). Despite its deep and narrow active site cavity, AChE is highly efficient in hydrolyzing acetylcholine (ACh). The authors describe their efforts to design potent inhibitors by colonizing the AChE gorge, which is a deep and narrow cavity at the bottom of the enzyme. They used molecular hybridization to extend binding at the catalytic site cavity (CAS) and then designed multisite inhibitors that span the entire gorge, reaching the peripheral anionic site (PAS). These multisite inhibitors exhibit subnanomolar potencies and can also modulate other targets in AD, such as BACE-1 and amyloidogenic proteins. The authors also discuss the design of multitarget agents based on AChE inhibitors, which can address multiple pathogenic events in AD, such as oxidative stress and neuroinflammation. Their results highlight the potential of AChE inhibitors as versatile templates for developing potent modulators of multiple therapeutic targets.The enzyme acetylcholinesterase (AChE) is a key therapeutic target for diseases with cholinergic deficits, such as Alzheimer's disease (AD). Despite its deep and narrow active site cavity, AChE is highly efficient in hydrolyzing acetylcholine (ACh). The authors describe their efforts to design potent inhibitors by colonizing the AChE gorge, which is a deep and narrow cavity at the bottom of the enzyme. They used molecular hybridization to extend binding at the catalytic site cavity (CAS) and then designed multisite inhibitors that span the entire gorge, reaching the peripheral anionic site (PAS). These multisite inhibitors exhibit subnanomolar potencies and can also modulate other targets in AD, such as BACE-1 and amyloidogenic proteins. The authors also discuss the design of multitarget agents based on AChE inhibitors, which can address multiple pathogenic events in AD, such as oxidative stress and neuroinflammation. Their results highlight the potential of AChE inhibitors as versatile templates for developing potent modulators of multiple therapeutic targets.