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The yeast Saccharomyces cerevisiae, a unicellular eukaryotic model, has enabled major breakthroughs in our understanding of a plethora of cellular and molecular processes. Today, a 're-invention' of its use in fundamental and applied research is paving the way for a better understanding of the mechanisms causing neurodegeneration. The increasing emergence of neurodegenerative disorders is becoming more and more problematic in our ageing society. Most prevalent is Alzheimer's disease (AD), affecting more than 35 million people worldwide (Abbott, Nature 475, S2-S4, 2011) and causing an enormous burden on a personal and communal level. The disease is characterized by two major pathological hallmarks: extracellular amyloid plaques consisting mainly of deposits of amyloid β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs), consisting mainly of aggregates of hyperphosphorylated tau protein. Despite the huge importance of thoroughly understanding the underlying molecular mechanisms of neurodegeneration, progress has been slow. However, multiple complementary research methods are proving their value, particularly with the work done with S. cerevisiae, which combines well-established, fast genetic and molecular techniques with the ability to faithfully capture key molecular aspects of neurodegeneration. In this review chapter, we focus on the considerable progress made using S. cerevisiae as a model system for Alzheimer's disease.