In the multistep process of cancer development, the concept that cancer stem cells are derived from normal stem cells that have gradually accumulated various genetic and epigenetic defects is gaining strong evidence. A number of investigations have identified molecular markers that, under normal conditions, are responsible for stem cell homeostasis but are also expressed in tumor "stem cell-like" subpopulations. In this regard, it was recently reported that a group of tumor-specific antigens known as cancer/testis antigens (CTAs) are expressed in human MSCs. It has long been stated that in normal tissue these antigens are exclusively expressed in germ cell precursors; however, based on these results, we suggest that CTAs are expressed at earlier stages during embryogenesis. The tumor-restricted expression of CTAs has led to several immunotherapeutic trials targeting some of these proteins. The clinical implications that these trials may have on the normal stem cell pools, as well as the immunologic properties of these cells, is to date poorly studied and should be considered.