The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death, including apoptosis, through transcription-dependent and transcription-independent mechanisms. On the one hand, nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes, such as NOXA, PUMA, BID, BAD, BIK, BAX, etc., whereas it inactivates the expression of anti-apoptotic BCL-2, BCL-XL, and MCL1, leading to mitochondrial apoptosis. On the other hand, cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the mitochondria. Apoptosis-related protein in TGF-β signaling pathway (ARTS), a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene, triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic stimuli. We recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic stress. ARTS in turn binds to p53, drives its mitochondrial localization, and enhances the interaction between p53 and BCL-XL, thereby promoting mitochondrial apoptosis. This review will illustrate the mechanisms of p53-induced mitochondrial apoptosis, offer some recently discovered new insights into the functions of ARTS in regulating mitochondrial cell death, and discuss the clinical significance of ARTS in cancer and non-cancer diseases.