Current technologies to identify and characterize circulating tumor cells (CTCs) and _ circulating tumor microemboli (CTMs) among hundreds of millions of leukocytes in the bloodstream can be classified into tumor-marker-dependent and -independent technology. Isolation by size of epithelial tumor cells (ISET) is a tumor-marker-independent technology, in which CTCs are isolated by filtration without use of tumor-associated markers, as a result of their large size relative to circulating blood leukocytes. ISET allows cytomorphological, immunocytological, and genetic characterization of CTCs and CTMs. It offers a number of advantages, including retention of cell morphology; non-antigen dependence; amenability of cells to further interrogation by immunolabeling, fluorescence in situ hybridization, and RNA/DNA analysis; ability to isolate CTMs; reliability. Therefore, morphological-analysis-based and antigen-independent ISET methodology can yield more accurate and objective characterization of epithelial-mesenchymal transition. We can evaluate efficacy of _chemotherapy and radiotherapy and other cancer-targeting therapies by using xenografts that are suitable models for mechanistic studies of ISET-isolated CTC/CTM biology. In addition, a new _ISET-based device could be designed to increase sensitivity to CTCs/CTMs greatly and reduce the number of CTCs/CTMs directly during the blood flow, thus decreasing the _possibility of tumor recurrence and metastasis while retaining normal blood cells. This article reviews recent advances and prospects in ISET methodology and provides new insights into ISET methodology, with important implications for the clinical management of cancer patients.