There are dozens of drugs in development for AD with billions of dollars invested. Despite the massive investment in AD drugs and a burgeoning pipeline, there have been more setbacks and failures than treatment successes. Areas covered: The classes of drugs that have failed to date include the monoclonal antibodies, the gamma secretase inhibitors, dimebon, neurochemical enhancers, and one tau drug. Data for these compounds were sought through a PubMed search and a clinicaltrials.gov search. Expert opinion: The obvious question to be posed is: Why are they failing? Is the treatment of symptomatic dementia too late? Are the therapeutic targets incorrect? Are the clinical methodologies imprecise, misleading, or inaccurate? This review summarizes the drugs that have failed during 2010-2015 and offers possible theories as to why they have failed.