In spite of ongoing research, Alzheimer’s disease (AD) remains an incurable disorder with a progressive course. Currently available treatment methods are mainly symptomatic, aimed at counteracting AD-related neurotransmitter changes. Among the potential combination therapies for AD, the largest body of evidence points to the concomitant use of a cholinesterase inhibitor (ChEI) and memantine. In short-term trials adding memantine to a previously administered ChEI (donepezil or rivastigmine) resulted in a significant improvement in cognitive functions, language, behavior and activities of daily living of moderate-to-severe AD patients, compared to ChEI monotherapy. The symptomatic benefits of combination therapy in earlier disease stages are dubious, administering it is nevertheless a common practice. The putative neuroprotective effects of memantine, potentially modifying the natural course of AD, particularly with early enough treatment initiation, might encourage physicians to use the combined treatment strategy even in mild AD. The results of long-term open-label studies prove that memantine-ChEI therapy can slow down the symptomatic progression of AD (both in terms of cognition and functional skills), delay nursing home placement, and significantly alleviate caregiver burden. However, one has to bear in mind that in Poland memantine use is approved only in moderate and severe AD. Combination therapy is perfectly safe, often even minimizing the risk of adverse effects associated with ChEI use. It’s cost-effectiveness has also been consequently demonstrated.