Metastasis is the major cause of mortality in cancer patients. Metastases can be present at the time of diagnosis or can occur years or decades after the removal of the primary tumor and treatment. This long latency in the manifestation of recurrent metastatic disease is explained clinically by the persistence of quiescent tumor cells that disseminated early in the course of the disease from the primary tumor to select distant organs. These residing disseminated tumor cells (DTCs) at distant organs lay dormant and asymptomatic until reawakened to form overt metastases. Importantly, the quiescent nature of these “hibernating” DTCs facilitates their resistance to conventional therapies that target actively dividing tumor cells. Therefore, unraveling the biology of dormancy and reactivation of the residing DTCs to life-threatening lesions is of utmost importance in order to develop new therapeutic strategies to prevent the recurrent metastatic disease from ever emerging or to better treat these recurrent cancers. The mechanisms underlying the biology of tumor dormancy and their reactivation to overt metastases are just beginning to emerge thanks to a growing appreciation of the potentially chronic nature of some cancers and the development of experimental model systems for their study. In this Research Topic, we will follow the journey of circulating tumor cells (CTCs) dispatching from the primary site until their successful lodging into a new and foreign site to become DTCs. We will explore the intrinsic mechanisms along with microenvironmental cues and niches that they encounter during their journey that may dictate their fate.