Background: The number of patients with second malignancies is growing and they represent about one in six out of all new cancers. Second malignancies can be categorized into three major groups according to the predominant etiological factor(s): (i) treatment-related, (ii) part of a syndrome and (iii) those due to shared etiologic exposures. Patients and Methods: This article focuses on radiation-induced malignancies with illustrative cases of thyroid, rectal cancer and sarcoma. Results: The detection and management of radiation-induced malignancies of some case scenarios are presented. Second malignancies are detected within previous radiation field and the time intervals from previous tumor vary from 8 to 21 years. Conclusion: Clinicians should aim to reduce radiation-induced malignancies by careful selection of patients and radiation techniques before radiotherapy. Subsequent vigilant followup and investigations can detect these radiation-induced malignancies early and, hence, result in successful treatment.