Genetic and biochemical evidence continues to implicate the production and accumulation of the Aβ42 peptide as the causative factor in Alzheimers disease (AD). Thus, a variety of strategies have been developed to decrease the production and/or aggregation of this peptide, which may be clinically useful for the treatment of this devastating disorder. Recently, the discovery that some non-steroidal anti-inflammatory drugs (NSAIDs) appear to selectively decrease the production of Aβ42 has opened a novel therapeutic avenue for AD treatment that may circumvent potential toxicity associated with long-term global inhibition of γ-secretase activity. One drug from this class of compounds, R-flurbiprofen, has advanced to phase 3 clinical trials and may soon provide insight into the viability of this strategy for the prevention or treatment of AD. Delineating the target and mechanism of these compounds is essential for developing new agents with increased potency and optimized pharmacologic properties. The evidence indicating that these chemicals modulate the production of Aβ peptides by directly interacting with the γ-secretase complex is summarized.