Lifespan of the versatile model system Caenorhabditis elegans can be extended by a decrease of insulin/IGF‑1 signaling, TOR signaling, mitochondrial function, protein synthesis and dietary intake. The exact molecular mechanisms by which these modulations confer increased life expectancy are yet to be determined but increased stress resistance and improved protein homeostasis seem to be of major importance. In this chapter, we explore the interactions among several genetic pathways and cellular functions involved in lifespan extension and their relation to protein homeostasis in C. elegans. Several of these processes have been associated, however some relevant data are conflicting and further studies are needed to clarify these interactions. In mammals, protein homeostasis is also implicated in several neurodegenerative diseases, many of which can be modeled in C. elegans.