The degree of metastatic outspread in malignant disease is one of the leading factors in determining the appropriate course treatment. Circulating tumor cells (CTCs) represent the population of cells that have acquired the means to gain access to the circulatory system, and the cell population ultimately responsible for the development of metastases at distant sites in the body. While promising as a biomarker for metastatic disease, the widespread study of CTCs has been limited by their rarity, as CTCs are reported to occur as infrequently as 1/mL of whole blood. In this text, we will discuss current and emerging technologies for the size-based enrichment of CTCs from whole blood, and compare some of the advantages and disadvantages of using a size-based approach to CTC enrichment versus affinity-based CTC enrichment platforms.