The question of whether some blood vessels in tumors of non-vascular origin are lined by cancer cells has been discussed for many years because of the relevance to metastasis, access of drugs to tumor cells, and the effectiveness of angiogenesis inhibitors. Most evidence favoring the existence of tumor cell-lined vessels has come from observations of standard histopathological tissue sections or from transmission and scanning electron microscopic studies. However, it has been difficult to determine convincingly just how abundant these vessels are in tumors. On the one hand, virtually the entire microvasculature is supposedly lined by tumor cells in aggressive uveal melanomas, assuming the presence of vasculogenic mimicry where tumor cells masquerading as endothelial cells create the channels for blood flow. On the other hand, morphometric studies using immunohistochemistry and green fluorescent protein-transfected tumor cells suggest that human colon cancer cells constitute only 3% of the vessel surface in tumors grown orthotopically in mice. This commentary weighs evidence that cancer cells are located in the wall of tumor vessels and discusses the pitfalls in identifying such vessels. Published data along with new observations illustrate the challenges of making an unequivocal identification of tumor cells in vessel walls. Taken together, current evidence suggests that cancer cells contribute at most only a small proportion of the lining of blood vessels in tumors and may be migrating through vessel walls or exposed by defects in the endothelium. Even in aggressive uveal melanomas, blood flow probably occurs mainly through channels lined by endothelial cells, not tumor cells, and most existing data do not support a functionally significant contribution of vasculogenic mimicry. Innovative new approaches that distinguish pleomorphic tumor cells from abnormal endothelial cells in vessel walls will help to define the incidence and importance of tumor cell-lined blood vessels in drug delivery and metastasis via the bloodstream.