The progressive increase in lifespan over the past century carries with it some adversity related to the accompanying burden of debilitating diseases prevalent in the older population. This review focuses on oxidative stress as a major mechanism limiting longevity in general, and healthful aging, in particular. Accordingly, the first goal of this review is to discuss the role of oxidative stress in limiting longevity, and compare healthful aging and its mechanisms in different longevity models. Secondly, we discuss common signaling pathways involved in protection against oxidative stress in aging and in the associated diseases of aging, e.g., neurological, cardiovascular and metabolic diseases, and cancer. Much of the literature has focused on murine models of longevity, which will be discussed first, followed by a comparison with human models of longevity and their relationship to oxidative stress protection. Finally, we discuss the extent to which the different longevity models exhibit the healthful aging features through physiological protective mechanisms related to exercise tolerance and increased β-adrenergic signaling and also protection against diabetes and other metabolic diseases, obesity, cancer, neurological diseases, aging-induced cardiomyopathy, cardiac stress and osteoporosis.