In the January 2010 issue of Science Translational Medicine, Phil Wong’s group reported a novel combination therapy targeting both BACE1 and gamma-secretase which may represent an effective and safe treatment strategy for Alzheimer’s Disease (AD). Only symptomatic treatments are now available for AD, and safe and effective therapies remain a great unmet need for patients with this illness. Although gamma- and beta-secretase (or BACE1) are well-recognized therapeutic targets for AD, untoward side effects associated with strong inhibition of these enzymes have raised concerns regarding their therapeutic potential. Although moderate decreases of either enzyme are not associated with side effects, they provide only modest benefits in the brain of a mouse model of amyloidosis (APPswe/PS1DE9 mice). Because the generation of amyloid requires both BACE1 and gamma-secretase, we tested whether moderate reductions of both enzymes would provide additive protection for the brain. Vivian Chow, Alena Savonenko and colleagues showed in this paper that moderate reductions of both BACE1 and gamma-secretase additively ameliorated the amyloid burden and attenuated cognitive deficits occurring in aged APPswe/PS1DE9 mice. Importantly, there is no evidence of mechanism-based toxicities associated with such therapeutic strategy in these mutant mice. Thus, we propose that this novel combination therapy of targeting both BACE1 and gamma-secretase may be an effective and safe treatment strategy for AD.