Multicellular organisms are composed of an interactive network of various tissues that are functionally organized as discrete organs. If aging were slowed in a specific tissue or organ how would that impact longevity at the organismal level? In recent years, molecular genetic approaches in invertebrate model systems have dramatically improved our understanding of the aging process and have provided insight into the preceding question. In this review, we discuss tissue and organ-specific interventions that prolong lifespan in the nematode C. elegans and the fruit fly Drosophila melanogaster. These interventions include reduced Insulin/IGF-1 signaling, knockdown of genes important for mitochondrial electron transport chain function and, finally, up-regulation of the Drosophila PGC-1 homolog. An emerging theme from these studies is that the intestine is an important target organ in mediating lifespan extension at the organismal level.