Metastasis—the spread of cancer to distant organs—is responsible for most cancer deaths. Current adjuvant therapy is based on prognostic indicators that stratify patients into defined risk groups. However, some patients believed to have a good prognosis nonetheless develop metastases, in some cases many years after apparently successful treatment of their primary cancer. This period of clinical dormancy leads to many questions about how best to manage patients, including how to better assign risk of late recurrence, how long to monitor patients, and whether some patients will benefit from extended therapy to prevent late recurrences. The development of targeted therapies with fewer side effects is leading to clinical trials aimed at determining the effectiveness of such long-term therapy. However, much remains to be learned about tumor dormancy. Experimental studies are shedding light on biological and molecular mechanisms potentially responsible for tumor dormancy. Emerging research into tumor initiating cells, immunotherapy, and metastasis suppressor genes, may lead to new approaches for targeted antimetastatic therapy to prolong tumor dormancy. An improved understanding of tumor dormancy is needed for better management of patients at risk for late-developing metastases.