The sensitivity of hematopoietic stem cells (HSCs) to toxic effects of cancer chemotherapy is one of the major roadblocks in cancer therapy. Moreover, the loss of HSC function in the elderly ("immunosenescence") is a major source of morbidity and mortality. Until recently, it was believed that HSCs were irreversibly damaged by the aging process. Recent work in mice shows that cycles of prolonged fasting (PF) of greater than 72 hr followed by refeeding can protect HSCs from the toxicity associated with chemotherapy and stimulate the proliferation of and rejuvenate old HSCs. A preliminary phase I trial in humans suggests that PF may confer benefit to people undergoing chemotherapy. These effects are at least partially mediated by lowered insulin-like growth factor-1 levels in the blood and stem cell microenvironment, which leads to lowered protein kinase A (PKA) activity. Reducing PKA levels or activity can replicate at least some of the effects of PF on HSCs. Shorter periods of fasting were not effective. PF represents a potentially profound, low-tech means to enhance cancer treatment and reverse aging of the immune system in the elderly. Because PF is likely to be stressful to the old and fragile, the development of PF mimetics may be warranted.