Frailty stands at the nexus of geriatrics and gerontology, and requires both basic biology and clinical knowledge for its analysis. Understanding frailty difficulties much more than simply adding another outcome measure in epidemiological studies. The major challenge is the identification of multiple feed-forward and feed-back signaling pathways involved in the maintenance of biological homeostasis in complex organisms that may fail with aging. The cause of frailty and loss of resilience is probably a progressive loss of redundancy in these response patterns and connections. Advances toward the development of a theoretical model that can potentially embrace the complexity of frailty should be highly encouraged, especially models designed to explain the biology of aging which can promote a better integration and communication between scientists who study this problem from different perspectives.