Cisplatin is a widely used cancer chemotherapeutic that promotes DNA damage-associated apoptosis. Although platinum compounds are known to form DNA adducts and provoke DNA damage, the molecular mechanism of cisplatin-induced cell death remains unclear. In this article, we show that the BH3-only protein Noxa is strongly transcriptionally upregulated in response to cisplatin and related platinum compounds. Cisplatin-induced Noxa expression was ERK dependent, but p53 independent, and inhibition of ERK activation markedly attenuated cisplatin-induced cell death, as well as Noxa expression. Furthermore, siRNA-mediated ablation of Noxa expression also inhibited cisplatin-induced cell death and permitted clonogenic survival. These observations reveal a novel ERK-regulated route to Noxa expression that is important for the cell killing activity of platinum-based chemotherapeutic drugs.