Model organisms have provided fundamental evidence that aging can be delayed and longevity extended. These findings gave rise to a new era in aging research aimed at elucidating the pathways and networks controlling this complex biological process. The identification of 9 hallmarks of aging has established a framework to evaluate the relative contribution of each hallmark and the interconnections among them. In this review, we revisit these hallmarks with the information obtained exclusively through the generation of genetically modified mouse models that have a significant impact on the aging process. We discuss within each hallmark those interventions that accelerate aging or that have been successful at increasing lifespan, with the final goal of identifying the most promising antiaging avenues based on the current knowledge provided by in vivo models.