Distant metastases are formed by tumor cells that shed from the primary tumor into the bloodstream. These circulating tumor cells (CTC) may be enumerated in a patients¿ blood. The number of CTC provides a prognosis, predicts a response to therapy and the expression of certain molecules in the CTC allows for determination of the most appropriate therapy. CellSearch, the standard assay for CTC enumeration from 7.5 mL of blood has shown feasibility of both these concepts, but finds no CTC in up to 50% of metastatic carcinoma patients. In this thesis we investigate several approaches to improve recovery of CTC. Archive data from several large clinical CTC trials were used to test alternative CTC definitions resulting in a higher number of CTC for similar or better prognostic value than the CellSearch definition. Flow cytometry was compared to CellSearch to evaluate whether a higher number of CTC is achievable by improved enrichment. The distribution function of CTC in metastatic patients was determined to estimate the effect of increased sample volume. The increase of sample volume by filtration of apheresis samples was investigated. An improvement to the CellSearch analyzer is presented to allow more accurate measurement of treatment targets on CTC. Increasing the number of CTC by a more inclusive CTC definition reduces the prognostic value of the CTC count when evaluating effectiveness of therapy. A potential threefold increase in EpCAM+CK+DNA+CD45- CTC by improved recovery will not be sufficient to find CTC in all metastatic carcinoma patients. Extrapolation of the EpCAM+CK+DNA+CD45- CTC distribution function in patients, predicts that increasing the sample volume to 5 liters of blood will result in recovery of CTC in 99% of metastatic patients. CTC enrichment by filtration of apheresis samples may allow for the sampling of such a blood volume, but we could not reach the required assay conditions due to sample age. It is critical for CTC enumeration that any cell included in the count is a CTC, even if this means that a large fraction of tumor cell (fragments) are not counted. To recover CTC in all patients, the sample volume must be increased dramatically. Sample age is critical, and CTC recovery in an extracorporeal circuit using antibody or physical based enrichment can circumvent this issue.