Circulating tumor cells (CTCs) were first discovered in 1869 but the clinical significance was not well appreciated. Over the past two decades, with rapid progresses in their biology and related technologies CTCs have reemerged as a major biomedical advance with great promises in tumor precision medicine. In this article, we start with introducing CTCs, their related CTC clusters and biology—origination, dissemination through circulation, heterogeneity, and their roles in tumor progression and metastasis. We then continue to detail the technological advances with CTC isolation, purification and characterization based on its biology characteristics. In the end, we discuss the potential clinical applications of CTCs in tumor precision and/or personalized medicine.