Because aging is a multifactorial, pleiotropic process where many interacting mechanisms contribute to the organismal decline, the candidate gene approach rarely provides a clear message. This chapter discusses some of the inherent complexity, focusing on aspects that impinge upon protein homeostasis and maintain a healthy proteome. We discuss candidate genes that operate in these pathways, and compare their actions in invertebrates, mice and humans. We highlight several themes that emerge from recent research—the interconnections of pathways that regulate aging, the pleiotropic effects of mutations and other manipulations of the candidate proteins and the tissue specificity in these pleiotropic outcomes. This body of knowledge highlights the need for multiple specific readouts of manipulating longevity genes, beyond measuring lifespan, as well as the need to understand the integrated picture, beyond examining the immediate outputs of individual longevity pathways.