In nearly 20 years, aside from cholinesterase inhibitors, memantine is the only drug approved for the treatment of Alzheimerʼs disease (AD). Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist that blocks pathological glutamate activity while permitting normal physiological function, thus preventing glutamate-induced excitotoxicity. Three Phase III pivotal trials demonstrated memantineʼs efficacy in treating moderate-to-severe AD, which led to its initial approval by the EMA in 2002 and US FDA in 2003. The recommended target dose is 10 mg twice daily. The US FDA recently approved an extended-release (ER) formulation of memantine for once-daily 28-mg dosing. Memantine ER was evaluated in a 24-week placebo-controlled trial of patients with moderate-to-severe AD, which found significant benefits for cognition, global assessment, behavior and caregiver burden, but not function. The most common adverse events were headache, dizziness, diarrhea, hypertension, anxiety and influenza. Overall, memantine in all formulations has a favorable safety/tolerability profile and is safe to use with cholinesterase inhibitors. Memantine ER has yet to be evaluated against conventionally dosed immediate-release memantine.