Circulating tumor cells (CTCs) are cancer cells that dissociate from primary and metastatic sites. The “liquid biopsy” analysis of CTCs is becoming attractive due to the easy access to blood. CTCs are thought to be the source of tumor progression and metastasis; genetic analysis of single CTCs allows the identification and characterization of tumor heterogeneity and malignancy. In clinical settings, the analysis of single CTCs can provide insights into tumor evolution and lead to precision cancer therapy. Genetic analysis of single cells is restricted by the low amounts of DNA (6–7 pg); therefore, whole-genome amplification (WGA) is required for downstream genetic analysis. In this chapter, we describe in detail the protocols from isolation of CTC from blood to WGA and quality check for downstream genetic analysis.