Apoptosis related protein in TGF-β signaling pathway (ARTS/septin 4 isoform 2) hereforth referred to as ARTS, was originally found to promote apoptosis induced by TGF-β, but later was shown to promote apoptosis induced by a wide variety of apoptotic stimuli. In vivo and in vitro studies revealed that ARTS-induced apoptosis is mainly executed through direct binding and antagonizing XIAP. High levels of XIAP are found in many types of cancers and often correlate with poor prognosis. ARTS was shown to function as a tumor-suppressor protein in human patients and mouse-tumor models. In particular, Septin 4/ARTS-deficient mice have increased tumor susceptibility and contain increased numbers of stem cells (SCs) and progenitor cells, apparently owing to their resistance towards apoptosis. Based on these results we propose that loss of proapoptotic ARTS may act as the 'first hit' initiating tumorigenesis in two distinct ways. First, loss of ARTS-mediated apoptosis leads to increased numbers of normal SCs. Elevated numbers of normal SCs may lead to increased cancer risk due to higher numbers of cellular targets available for transforming mutations. Second, after these SCs acquire additional transforming mutations and become cancer SC (CSCs), they are more likely to survive in the absence of ARTS owing to increased resistance toward apoptosis. A combination of these two mechanisms, over time, is expected to significantly increase tumor risk. Because CSCs appear to share phenotypic markers with normal SCs, targeting the signaling pathways that affect normal SC development and maintenance can serve as a useful approach towards true eradication of cancer. In this article we describe the role of ARTS in apoptosis and cancer, with focus on its potential role as a CSC marker and as a potential target for anticancer and anti-CSC therapy.