In the June 2015 issue, Nature Neuroscience published a pair of point-counterpoint Perspective articles taking a closer look at the pros and cons of the amyloid hypothesis of Alzheimer’s disease (AD). In one piece, Dr. Karl Herrup illustrated the many deficiencies in the Aβ hypothesis and suggested that the time may be right to re-evaluate our overreliance on this particular view of AD pathogenesis. In the counterpoint, Drs. Erik Musiek and David Holtzman argue that the current evidence still supports the Aβ as the key initiator of AD pathology. Here, we present these two pieces, as well as the first few videos from the Society for Neuroscience panel event, and welcome further comment and discussion of this pervasive hypothesis and its actual role in disease pathogenesis.