Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers apoptosis upon binding to its ligand or when overexpressed. Its expression is induced by certain small molecule drugs, including celecoxib, through mechanisms that have not been fully elucidated. The current study has revealed a novel ERK/ribosomal S6 kinase (RSK)-dependent mechanism that regulates DR5 expression primarily using celecoxib as a DR5 inducer. Both C/EBP homologous protein (CHOP) and Elk1 are required for celecoxib-induced DR5 expression based on promoter deletion and mutation analysis and siRNA-mediated gene silencing results. Co-expression of both CHOP and Elk1 exhibited enhanced effects on increasing DR5 promoter activity and DR5 expression, indicating that CHOP and Elk1 co-operatively regulate DR5 expression. Because Elk1 is an ERK-regulated protein, we accordingly found that celecoxib increased the levels of phosphorylated ERK1/2, RSK2, and Elk1. Inhibition of either ERK signaling with a MEK inhibitor or ERK1/2 siRNA, or RSK2 signaling with an RSK2 inhibitor or RSK2 siRNA abrogated DR5 up-regulation by celecoxib as well as other agents. Moreover, these inhibitions suppressed celecoxib-induced CHOP up-regulation. Thus, ERK/RSK-dependent, CHOP and Elk1-mediated mechanisms are critical for DR5 induction. Additionally, celecoxib increased CHOP promoter activity in an ATF4-dependent manner, and siRNA-mediated blockade of ATF4 abrogated both CHOP induction and DR5 up-regulation, indicating that ATF4 is involved in celecoxib-induced CHOP and DR5 expression. Collectively, we conclude that small molecules such as celecoxib induce DR5 expression through activating ERK/RSK signaling and subsequent Elk1 activation and ATF4-dependent CHOP induction.