Human lifespan is limited by aging of both mitotic and post-mitotic cells. These two forms of aging may occur by distinct or overlapping mechanisms. Telomere erosion has been shown to limit the proliferative lifespan of human somatic cells. Other vertebrates, such as mice, possess robust telomerase activity in most cell types and their somatic cells display finite replicative lifespans as a consequence of other forms of macromolecular damage. Genetic analysis in humans, mice and yeast has provided clues regarding pathways that may affect a cell's replicative lifespan. In addition, analysis of the means by which germ cells maintain their effervescent character may provide a deeper understanding of how replicative aging occurs in somatic cells.