Development of a second malignancy is one of the most serious late effects in survivors of both childhood and adult-onset cancers. Patterns of second malignancy risk across the age spectrum can differ in terms of the types of second malignancies observed, magnitude of the risks, the latency period, associated risk factors, and modifying influences. Potential explanations for the varying risk patterns by age include differences in susceptibility of individual tissue/organ to carcinogenesis based on stage of development and level of tissue maturity, microenvironment, attained age, and lifestyle factors. A thorough understanding of these differences is essential when considering treatment modifications in newly diagnosed cancer patients who are aimed at reducing the risk of second malignancy and other late effects without compromising cure. Moreover, an understanding of the variations in second cancer risk according to age at treatment is important in customizing patient follow-up.