Aging is defined as a time-dependent functional decline that occurs in many physiological systems. This decline is the primary risk factor for prominent human pathologies such as cancer, metabolic disorders, cardiovascular disorders, and neurodegenerative diseases. Aging and age-related diseases have multiple causes. Parabiosis experiments, in which the circulatory systems of young and old mice were surgically joined, revealed that young plasma counteracts aging and rejuvenates organs in old mice, suggesting the existence of rejuvenating factors that become less abundant with aging. Diverse approaches have identified a large number of plasma proteins whose levels differ significantly between young and old mice, as well as numerous rejuvenating factors that reverse aged-related impairments in multiple tissues. These observations suggest that increasing the levels of key rejuvenating factors could promote restorative biological processes or inhibit pathological degeneration. Inspired by such findings, several companies have begun selling “young blood transfusions,” and others have tested young plasma as a treatment for Alzheimer’s disease. Here, we summarize the current findings regarding rejuvenating factors.