Eighteen percent of incident malignancies in the United States are a second (or subsequent) cancer. Second primary neoplasms (SPNs), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, genetic factors, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs.