Presenilins form the catalytic part of the γ-secretases, protein complexes that are responsible for the intramembranous cleavage of transmembrane proteins. The presenilins are involved in several biological functions, but are best known for their role in the generation of the β-amyloid (Aβ) peptide in Alzheimer's disease and are therefore thought to be important drug targets for this disorder. Mutations in the presenilin genes cause early-onset familial Alzheimer's disease, but mutation carriers have substantial phenotypic heterogeneity. Recent evidence implicating presenilin mutations in non-Alzheimer's dementias, including frontotemporal dementia and Lewy body dementia, warrants further investigation. An increased understanding of the diversity of the molecular cell biology of the γ-secretase complex and the effects of clinical mutations in the presenilin genes might help pave the way for improved development of drugs that are designed to target γ-secretase enzymatic activity in Alzheimer's disease and potentially in other neurological diseases.