Immunotherapies targeting the amyloid-β (Aβ) peptide in Alzheimer's disease (AD) have consistently been effective in mouse studies and shown promise in clinical trials, although some setbacks have occurred. First, encephalitis was observed in a small subset of patients. More recent autopsy data from a few subjects suggests that clearance of Aβ plaques may not halt cognitive deterioration once impairments are evident, emphasizing the need for other more effective approaches at that stage of the disease. Another important target in AD is the neurofibrillary tangles and its precursors, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As Aβ and tau pathologies are likely synergistic, targeting both together may be more effective, and perhaps essential as early diagnosis prior to cognitive decline is currently unavailable. Also, Aβ immunotherapy results in a very limited indirect clearance of tau aggregates, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that active immunization targeting an AD phospho-tau epitope reduces aggregated tau in the brain and prevents/ slows progression of the tangle-related behavioral phenotype, including cognitive impairment. These antibodies enter the brain and bind to pathological tau within neurons although the therapeutic effect may at least in part be due to clearance of extracellular tau that may have biological effects. We are currently clarifying the mechanism of these promising findings, determining its epitope specificity as well as assessing the feasibility of this approach for clinical trials.