A multitude of neuropathological studies has established a robust link between Down syndrome and Alzheimer’s disease. Through massive projections to the entire cortex and hippocampus, the monoaminergic-systems exert a powerful modulatory effect on brain regions vitally important for cognition. Nevertheless, substantial evidence demonstrates these systems are inherently vulnerable to neurodegeneration, particularly in Down syndrome and Alzheimer’s disease. Accordingly, abnormalities in the structure and function of subcortical monoaminergic systems constitute a common characteristic of both disorders. Underlying these deficits are neuropathological changes in the locus coeruleus, ventral tegmental area, substantia nigra and raphe and tuberomamillary nuclei. Fortunately, preclinical and clinical studies suggest that pharmacotherapies targeting of these systems may provide symptomatic relief along with disease modifying effects in Down syndrome and Alzheimer’s disease.