Apoptosis plays particularly important roles in tumorigenesis through various mechanisms. Apoptosis can be initiated by both extrinsic and intrinsic signals centered in and coming from the mitochondria. Antiapoptotic proteins promote tumor progression, and the occurrence and progression of tumors are closely related to antiapoptotic protein expression. As the only member of the septin gene family with proapoptotic function, apoptosis-related proteins in the TGF-β signaling pathway (ARTS) has received extensive attention for its unique structure. In contrast, unlike other known inhibitors of apoptosis protein (IAP) antagonists, ARTS exhibits a stronger tumor suppressor potential. Recent research has shown that ARTS can bind and inhibit XIAP and Bcl-2 directly or assist p53 in the degradation of Bcl-XL. Here, we review recent advances in the molecular mechanisms by which the proapoptotic protein ARTS, with its unique structure, inhibits tumorigenesis. We also discuss the possibility of mimicking ARTS to develop small-molecule drugs.