Alzheimer’s disease (AD) is a major and increasing burden on families, communities, and national health budgets. Despite intensive and extended research, there is still widespread debate about its cause(s), and no effective treatments exist. Familial (inherited, mainly early onset) and sporadic (mainly late onset) forms of the disease exist, and it is uncertain to what extent they are related. Transgenic mouse models have dominated the investigation of this disease, but their validity can be questioned. Numerous alternative models exist that can provide valuable information on the molecular and cellular basis of AD. In this chapter, we review the various invertebrate, nonmammalian vertebrate, and mammalian models and how these have been used to investigate this disease. We examine the strengths and weaknesses of these various model systems. Of course, animal models never completely reflect the true nature of a human disease, but progress in understanding and finding preventative and ameliorative treatments for AD is hindered by the lack of a convincing hypothesis for the cause of this complex condition. ; Mengqi Chen, Doris Kretzschmar, Giuseppe Verdile, Michael Lardelli