The role of circulating tumor cells (CTCs) has begging to be recognized the last few years.Still during time several approaches have been developed in purpose to identify, enumerate and analyze these cells.Even more recently a subset from the primary tumor as well as of the CTCs, has been recognized as tumor initiation cells known as cancer stem cell like.It has been pointed out from the scientific community that the accurate identification of all subset of CTCs and the analysis of CSCs may lead us to a better understanding of cancer development and progression.The research effort that have been done so far revealed that only by utilizing methods and assays that allow us by negative selection,to identify and isolate all sub-clones of CTCs we have the majority of information and data that allow us to detect new drugable target as well as to apply personalized treatment to patient.But to that point it is essential to recognize the limitation of such approaches.Specifically it has been established well the plasticity of CTCs to shift to CSCs and the other way around.Additionally it is equally important to recognize the difficulty based on the fact that CTCs may arise from the primary tumor as well as from metastatic tumor.Hence the information that we may be able to generate derived from all tumors on a patient.Finally the plasticity of CTCs itself varies which allow the random shifting from CTCs to CSC phenotype cells and the reverse.Hence the role of CTCs and CSCs has been pointed out, but well established methods and techniques required which will provide accurate, repeatable and reliable information which may lead not only to better understanding of cancer progression, but also to establish tailor made therapies to patient increasing the disease free survival (DFS), time to relapse (TTR) as well as the overall survival (OS) rates.