Neoplasms are derived from normal tissues of the body by cellular transformation. Tumors often represent a less differentiated or an undifferentiated version of the histology of the neoplasms original tissue. Primary tumor(s) may spread by direct extension or by metastasis. For the purpose of this review, second primary tumors will be defined to exclude metastatic lesions or recurrences from an original primary tumor. Second primary tumors arise in several different clinical situations that basically are the result of either inherited or acquired genetic mutations. Second primary tumors may develop soon or very late after treatment of the first primary tumor and may reflect an underlying genetic or immunologic defect in the patient, treatment related genetic damage, or environmental exposure to carcinogens. With the greater success of modern chemotherapy and radiotherapy in achieving long-term remissions in many patients, second primary tumors are a rapidly developing disease-category. This paper will review the clinical circumstances associated with a significantly higher incidence of second primary tumors in patients with an initial primary tumor.