According to recent epidemiological studies, malignant diseases represent the second cause of mortality worldwide and metastasis is the main cause of morbidity and mortality in most cancers. Even if the concept of "cancer stem cells" (CSCs) was anticipated by the genius of Rudolph Virchow, the father of modern pathology, more than 150 years ago, it is only in last few years that that scientists have begun to develop strategies aimed at inhibiting CSCs at a molecular level, the only way cancer can truly be attacked, by crossing the border between histology and molecular biology. The current concise review aims at emphasizing the main characteristics of tumor initiating cells, bridging the basic science to clinical hematology and oncology.