Genomic instability has been considered to be one of the prominent factors for carcinogenesis and the development of a number of degenerative disorders, predominantly related to the aging. The cellular machineries involved in the maintenance of genomic integrity such as DNA repair and DNA damage responses are extensively characterized by a large number of studies. The failure of proper actions of such cellular machineries may lead to the devastating effects mostly inducing cancer or premature aging, even with no acute exogenous DNA damage stimuli. In this review, we especially focus on the pathophysiological aspects of the defective DNA damage responses in carcinogenesis and premature aging. Clear understanding the causes of carcinogenesis and age-related degenerative diseases will provide novel and efficient approaches for prevention and rational treatment of cancer and premature aging.