AbstractDespite significant advances in the understanding of the molecular genetics and molecular cell biology of Alzheimer’s disease there is still no disease modifying therapeutic available to patients. Improved understanding of the disease biology and a string of late stage clinical failures have led to a re-appraisal of the original amyloid cascade hypothesis which formed the basis of many of the failed clinical approaches. While misfolded proteins Abeta and Tau are still believed to be critical factors in the disease process a complex picture of cellular changes is emerging involving both proteostatic failure and neuroinflammatory processes in response to proteopathic stress. As these areas lead to the identification of novel targets for drug discovery, robust and reproducible biological validation will be key to successful and productive future drug discovery. This presentation will consider both established and novel targets and the challenges and opportunity they represent for the development of effective treatments of Alzheimer’s disease.