Homeostasis is a key feature of cellular lifespan. Maintenance of cellular homeostasis influences the rate of aging and its efficiency is determined by the cooperation between protein stability and resistance to stress, protein refolding, protein repair and proteolysis of damaged proteins. Protein degradation is predominately catalyzed by the proteasome which is responsible for cell clearance of abnormal, denatured or in general damaged proteins as well as for the regulated degradation of short-lived proteins. Impaired proteasome function has been tightly correlated to aging both in vivo and in vitro and thus, emphasis has been given recently in identifying ways of its activation. A number of studies have shown that the proteasome can be activated by genetic manipulations as well as by factors that affect either its conformation and stability or the expression of its subunits and the rate of proteasome assembly. This “readjustment” has been shown to have a great impact on retention of cellular homeostasis since it promotes lifespan extension. This chapter focuses on protein homeostasis and its direct link to proteasome function, dysfunction and manipulation and provides insights regarding the activation of proteasome-mediated protein degradation that, in turn, ensures health maintenance.