By some estimates moderate-to-severe Alzheimer's disease accounts for 50% of all patients with Alzheimer's disease. However, there are numerous issues that remain to be resolved in the management of patients with more advanced Alzheimer's disease. The first prospective, randomised, controlled trial of the cholinesterase inhibitor donepezil in more advanced Alzheimer's disease has reported quite encouraging results, with further studies being undertaken. Post-hoc analyses of rivastigmine and galantamine in patients with more advanced Alzheimer's disease have supported the hypothesis that acetylcholinesterase inhibitors are likely be efficacious in this subgroup. Memantine, a glutamate NMDA receptor antagonist, is newly licensed in Europe for the treatment of more advanced Alzheimer's disease and will provide the first non-cholinesterase inhibitor option for the treatment of Alzheimer's disease. The combination of donepezil and memantine has been shown to have superior efficacy than donepezil alone in this severe Alzheimer's disease subgroup, potentially supporting a role for dual treatment in more advanced Alzheimer's disease. Further studies of all aspects of more advanced Alzheimer's disease are clearly needed. The problems of translating clinical trial results to routine clinical practice are even more complex and challenging in this patient group, with the true impact of any one given treatment ranging over a spectrum of clinical domains from improved cognition to reduced caregiver burden. Increased attentiveness by clinicians to treatment response across this multidisciplinary spectrum in more advanced Alzheimer's disease is warranted.