The in vitro and in vivo characterization of adult stem cells has allowed researchers to identify certain specific functional features to each tissue-specific stem cell. Moreover, recent studies revealed that their malignant counterparts, the cancer progenitor cells with stem cell-like properties, may assume a crucial role for the initiation and progression of locally invasive cancers into disseminated and incurable disease states. Therefore, a new direction in cancer research appears necessary in considering the critical functions of cancer progenitor cells. In this review, we discuss recent concepts on the critical roles of tumorigenic and migrating cancer progenitor cells in carcinogenesis. Particularly, we describe the tumorigenic cascades that are frequently activated through the interplay of diverse hormones, growth factors, cytokines and integrins in cancer progenitor cells versus their further differentiated progeny. The emphasis is on the oncogenic signaling pathways activated during the localized cancer progression and micrometastatic events involved in tumor formation at distant sites such as bone marrow. Of therapeutic interest, important information for the selective molecular targeting of cancer progenitor cells, which must now be considered in developing new effective diagnostic and prognostic methods and curative treatments against the most locally advanced and metastatic cancers, is also described.