Circulating tumour cell (CTC), a rare subpopulations of tumour cells, plays a significant role in cancer metastasis and recurrence. The current review focuses on information of CTCs detection, enrichment, genome sequencing and investigating on clinical significance of CTCs sequencing in monitoring progress of patients with cancer. Tissue biopsy is not always favorable for monitoring cancer recurrence and metastases and can be difficult and risky for the patient’s condition. On the other hand, enrichment and characterization of CTC could be effective in these circumstances. Accordingly, a number of detection (physical, immunological etc.), isolation (laser capture microdissection, DEPArray Di Electro phenetic array, fluorescence-activated cell sorting etc.) and enrichment platforms (Cellsearch, MagSwepeer, CTC-Chip etc.) have been developed. In addition, technologies for phenotypic characterization and genomic profiling (Tang’s method, Smart-seq, Cel-seq etc.) at single-cell level has being established followed by genomic amplification. Importantly, numerous preclinical and clinical studies showed effective prognostic and predictive implications of molecular characterization of CTCs. CTC’s sequencing has been successfully used as an effective tool to monitor genomic variations in the primary and metastatic tumours, thereby could predict the therapy resistance, recurrence of tumours. The genes expression profiles, stratification of cancers as well as identify the cancer cells with potential to undergo epithelial-mesenchymal transition (EMT) could also be identified. In addition, detection of mutational variants of CTCs by genome sequencing infer the therapeutic outcome and patient’s survival. Therefore, CTC sequencing has potential to be used as a liquid biopsy tool for management of patients with cancers in clinical settings.