The survival of children with cancer has improved dramatically in the last decades. Survivors of childhood cancer are at increased risk of long-term complications of therapeutic exposure. Second malignant neoplasms are one of the most severe side effects of cancer treatment. The frequency and type of secondary cancers may vary depending on the initial diagnosis, treatment administered and genetic predisposition. This review highlights the risk factors in the development of SMNs in survivors of pediatric cancers and their differences according to primary cancer type, genetic predisposition and treatment admistered. Finally, the review emphasizes the need for life-time follow-up of survivors of childhood cancer for the development of second malignancies.