Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide classically implicated in the regulation of energy homeostasis, sleep–wake cycle and motivated behaviors. Over the last 30 years, an increasing amount of evidence has revealed a complex, non-linear role in memory processing. In this mini-review, we summarize experimental findings on the multifaceted influence of MCH on memory, highlighting how this neuropeptide can promote consolidation by improving synaptic efficacy, induce the forgetting of hippocampus-dependent memories during REM sleep or negatively regulate memory formation. We also discuss emerging evidence linking MCH dysregulation to the pathophysiology of Alzheimer’s disease (AD). Early interest in MCH as a cerebrospinal fluid biomarker has been superseded by non-invasive blood assays. Recent data, however, suggest therapeutic potential and a unique pathological vulnerability. While emerging evidence suggests MCH somata may show early resilience, their axonal projections are severely compromised by amyloid pathology. Ultimately, tau pathology appears to drive late-stage somatic degeneration and reduced activation during REM sleep. Importantly, activating surviving MCH neurons has been shown to restore sleep architecture in preclinical models, offering a potential therapeutic target for sleep disturbances. In conclusion, decades of basic memory research together with human and preclinical studies identify the MCH system as an important neuromodulatory network for understanding the memory and sleep alterations characteristic of AD.