Circulating tumor cells (CTCs) are cancer cells that enter blood or lymphatic vasculatures and circulate through the bloodstream or lymph stream for potential dissemination into distant organs (Schuster et al., 2021, Visal et al., 2022). The cellular heterogeneity of CTCs is governed by a complex interplay between cancer cell intrinsic and immune microenvironmental factors of genomic and epigenomic alterations, transcriptomic reprogramming, proteomic changes, and post-translational and metabolomic modifications (Burrell et al., 2013, D'oronzo et al., 2019, Huang et al., 2022, Paoletti et al., 2018, Stewart et al., 2020, Tsai et al., 2021). CTCs are detected as single cells and multicellular clusters, the latter of which show enhanced metastatic potential, including homotypic clusters with CTCs only and heterotypic clusters of CTCs aggregating with other blood cells (Pereira-Veiga et al., 2022, Schuster et al., 2021). The plasticity (stemness) features and the multicellular clustering phenotypes of CTCs are closely related to the potential in mediating metastasis and clinical outcomes (Lin et al., 2021, Theodoropoulos et al., 2010). This heterogeneity not only endows CTCs with the ability to adapt and survive in the circulation, but also to invade and colonize distant organs. As a non-invasive liquid biopsy, CTCs hold immense potential for clinical applications, including diagnosis, prognosis, and therapeutic monitoring/targeting. The detection and characterization of CTCs have paved the road for personalized cancer management and novel therapeutic interventions (Ring et al., 2023, Rupp et al., 2022). While the detection of rare CTCs is summarized in a separate article, this review will highlight the new progress in understanding the molecular and cellular mechanisms underlying CTC functions and clinical relevance.