Circulating tumor cells (CTCs) that detach and migrate from primary tumors are implicated in the metastatic spread of cancer. The identification of CTCs in peripheral blood samples has been associated with poor survival outcomes in various cancer types. As a readily accessible source of tumor tissue there is a vast potential to develop CTCs as a biomarker to advance cancer diagnosis, prognosis and the development of novel and targeted therapies. The fact that CTCs occur as extremely rare events in whole blood presents a technical challenge for characterization, requiring enrichment techniques that are both highly sensitive and sufficiently specific. The culture and expansion of CTCs is desirable as a means of yielding a population suitable for comprehensive functional characterization and drug testing. Reports of successful in vitro culture of CTCs are rare, but various approaches have been attempted and significant progress has been made. The development of protocols for reliable and efficient culture of viable CTCs will advance our biological understanding of cancer metastasis and facilitate the development of personalized therapies.