Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective prevention or treatment. The prediction that the number of U.S. patients with AD will triple to approximately 14 million over the next 50 years underscores the urgent need to explore novel therapeutic strategies for AD. The beta-amyloid protein (Abeta) accumulation and accompanying inflammation appear to play key roles in initiating the neuronal degeneration that underlies the signs and symptoms of AD. Interventions geared toward reducing Abeta accumulation and inflammatory responses should delay or prevent the onset of the clinical disease. Recently, several research groups, including ours, have shown that vaccination with Abeta results in a significant lowering of the Abeta burden in the brains of APP transgenic mice and, in some studies, improvement in their cognitive deficits. Our study described a novel approach, namely mucosal (intranasal) Abeta vaccination. Precisely how Abeta vaccination chronically lowers Abeta levels and reduces Abeta-associated pathology remains unclear. Here, we provide an overview of these studies, with particular emphasis on our work with intranasal Abeta vaccination. Examples of other intranasal vaccines and mucosal adjuvants are presented. Taken together, these data have implications for the future development of an intranasal Abeta vaccine for humans.