Alzheimer's disease (AD) is the most common cause of age-related cognitive decline. Both active and passive immunization paradigms have illustrated the potential to prevent and reverse established AD pathology in transgenic and non-transgenic animal models of AD. Follow-up studies have shown that changes in amyloid burden observed with immunization could rescue cognitive deficits in both young and aged mice. Despite the success of immunotherapy in animal models, clinical trials were halted early. It has become clear that more preclinical work was needed before initiating trials, as most of the adverse events observed in patients could have been predicted using animal models. Despite these setbacks, clinical trials have demonstrated the utility of amyloid-beta (Abeta) vaccination in reducing amyloid pathology and potentially reducing cognitive decline. Several novel approaches to immunotherapy, including modified immunogens, adjuvants and modes of administration have been designed, which hold promise for human testing. Clinical trials using a safer vaccine, which is potent enough to elicit a robust antibody response in the absence of encephalitis may prove effective in mitigating progressive neurodegeneration seen in AD. If so, Abeta vaccination could supplant current symptomatic treatment and represent one of the first therapeutic options for AD based on the amyloid cascade hypothesis.