Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease of the production of amyloid-beta (Aβ), which is a hallmark of Alzheimer’s disease (AD). As a result, since its discovery and characterization in 1999, BACE1 has been a prime drug target for AD. For the last quarter century, many preclinical studies and clinical trials of BACE inhibitors have taken place. In the 2010s, six BACE inhibitors entered Phase II/III clinical trials, but unfortunately, all were discontinued due to futility or safety concerns. An unintended and surprising side effect of BACE inhibitors was cognitive worsening, but this was found to be reversible after treatment cessation. Since the termination of the trials, researchers have continued to study BACE1 and continue to learn more about its physiological functions with respect to its many substrates. Blocking BACE1 cleavage of one or more of these substrates is likely the cause of the reported cognitive worsening. With more knowledge of these substrates, it may be possible to design BACE1-oriented therapies that do not have this unacceptable side effect. Further, there are some important considerations for planning future BACE1-oriented trials that are more likely to succeed. These trials should be conducted in a primary prevention setting (go earlier) and at much lower doses, to avoid side effects while still lowering Aβ sufficiently to slow down or stop preclinical AD from turning into clinical AD.