Caloric restriction without malnutrition extends lifespan and delays the onset of age-associated disorders in diverse species, from unicellular organisms to laboratory mice and rats. Until recently, evidence of the translatability of CR’s effects to human health has been a critical gap in CR research. In the late 1980s two parallel rhesus monkey caloric restriction (CR) studies were initiated to determine the effect of CR on resistance to illness and mortality in nonhuman primates. With more than 20 years of longitudinal data accrued, both studies have demonstrated improvements in health in CR animals compared to controls, significant in the University of Wisconsin (UW) study, and approaching significance in the National Institute on Aging (NIA) study. The impact of CR on survival in nonhuman primates; however, is a point of departure in the two studies. In 2009 the UW-Madison-based research team reported improved survival for animals on CR. In contrast, the NIA-based research team reported in 2012 that there was no difference in survival between CR and Control monkeys. Here we present a comparison of key differences in study design that could explain differences in survival outcome, including the genetic origin of the study cohort, age of onset for the dietary intervention, dietary composition, feeding regimens, and protocols for animal husbandry. The relative contributions of these differences to study outcomes will be discussed, and NIA and UW perspectives on the impact of these findings on CR research and its potential to reveal insights into human health will be presented.