Tau hyperphosphorylation is thought to play an important role in the etiology of Alzheimer's disease by facilitating the formation of neurofibrillary tangles. Reducing phosphorylation through kinase inhibition has therefore emerged as a target for drug development, but despite considerable efforts to develop therapeutic kinase inhibitors, success has been limited. An alternative approach is to develop pharmaceuticals to enhance the activity of the principal phospho-tau phosphatase, phosphoprotein phosphatase 2A (PP2A). In this article we review evidence that this mechanism is pharmacologically achievable and has promise for delivering the next generation of Alzheimer's disease therapeutics. A number of different chemotypes have been reported to lead to enhanced PP2A activity through a range of proposed mechanisms. Some of these compounds appear to act directly as allosteric activators of PP2A, while others act indirectly by inhibiting the binding of PP2A inhibitors or by altering post-translational modifications that act in turn to regulate PP2A activity towards phospho-tau. These results indicate that PP2A may provide a useful target that can be safely, selectively and effectively modulated through pharmaceutical intervention to treat Alzheimer's disease.