The requirement for an intact p53 signaling pathway to sense tumor-promoting DNA damage is evident from over 20 years of molecular, cellular, and whole animal studies. Without a doubt, p53's major contribution in maintaining the genomic integrity of multicellular organisms is through transcriptional regulation of genes required for cell cycle arrest, DNA repair, and apoptosis. Nonetheless, evidence is mounting that p53 has an extranuclear role in the cytoplasm to induce apoptosis, perhaps coupled to its transcriptional effects, or conceivably at instances when transcription is not optimal or possible. This phenomenon, transcription-independent p53-induced apoptosis (TIPA), has been described for almost 10 years, yet little is known about mechanisms by which p53 can directly engage the apoptotic cascade in the absence of transcription. Here we will explore what is currently known about TIPA learned from various p53 mutants and truncations, along with discussing several proposed mechanisms.