Pathological aggregation of the microtubule-associated protein tau and accumulation of neurofibrillary tangles (NFT) and other inclusions containing hyperphosphorylated tau are defining histopathological features of Alzheimer disease (AD) and many other neurodegenerative diseases collectively known as tauopathies. The toxicity of tau aggregates has been demonstrated in vitro and in vivo; thus, their clearance by immunotherapy holds clinical promise. Published studies, which are limited in number, have exclusively focused on the clearance of hyperphosphorylated large tau aggregates, e.g., NFT. However, recent studies using human tissues and mouse models have questioned the toxicity and the presumed role of NFT in the progression of tauopathies and challenged the view of tangles as toxic species in the brain. Together, these novel studies have demonstrated that prefilamentous tau oligomers rather than NFT play a crucial role in these disorders. Here, we summarize recent advances in this new field, highlight the role of tau oligomers and their potential as a therapeutic target for the treatment of AD and other neurodegenerative tauopathies, and discuss the challenges that lie ahead.