Down syndrome (DS) is the most common chromosomal abnormality in humans. DS is characterized by a number of phenotypes, including the development of Alzheimer's disease-like pathology and immunological, hematological and cardiovascular alterations. Apoptosis or programmed cell death is physiologically involved in development and aging, as well as in numerous pathological processes. Altered apoptosis has been proposed as a putative mechanism underlying many DS phenotypes. Evidence from human and animal studies indicates that apoptosis does not have a prominent role in the disturbances found in brain development in trisomy 21. However, alterations in apoptosis have been associated with neurodegeneration in the aging DS brain, with impairments in general growth and with immunological, cardiovascular and oncological alterations. Altered apoptosis in DS is likely to be the result of the interplay between several chromosome 21 (Hsa21) and non-Hsa21 genes. The interplay between these genes may affect physiological programmed cell death either directly, by modifying the activity of the apoptotic pathways, or indirectly, by inducing degeneration and rendering the cell more vulnerable to apoptosis-inducing factors.